Natural compounds targeting nuclear receptors for effective cancer therapy

Abstract

Human nuclear receptors (NRs) are a family of forty-eight transcription factors that modulate gene expression both spatially and temporally. Numerous biochemical, physiological, and pathological processes including cell survival, proliferation, differentiation, metabolism, immune modulation, development, reproduction, and aging are extensively orchestrated by different NRs. The involvement of dysregulated NRs and NR-mediated signaling pathways in driving cancer cell hallmarks has been thoroughly investigated. Targeting NRs has been one of the major focuses of drug development strategies for cancer interventions. Interestingly, rapid progress in molecular biology and drug screening reveals that the naturally occurring compounds are promising modern oncology drugs which are free of potentially inevitable repercussions that are associated with synthetic compounds. Therefore, the purpose of this review is to draw our attention to the potential therapeutic effects of various classes of natural compounds that target NRs such as phytochemicals, dietary components, venom constituents, royal jelly–derived compounds, and microbial derivatives in the establishment of novel and safe medications for cancer treatment. This review also emphasizes molecular mechanisms and signaling pathways that are leveraged to promote the anti-cancer effects of these natural compounds. We have also critically reviewed and assessed the advantages and limitations of current preclinical and clinical studies on this subject for cancer prophylaxis. This might subsequently pave the way for new paradigms in the discovery of drugs that target specific cancer types.

1 Introduction

Neoplasms are multicellular and multifactorial pathological conditions that cause a massive public health burden across the world with an estimated 19.3 million newly diagnosed cases and 10.0 million deaths [1]. Drastic advancements in genomic, metabolomic, and proteomic research have revealed that neoplastic cell arises as a result of perturbations in multiple signaling pathways as well as pervasive genetic and epigenetic alterations in various genes that remain dormant for several years before developing the clinically diagnosable disease [2]. The heterotypic signaling machinery detailing the intercommunication between neoplastic cells and stromal cells within tumors to assemble and collaborate to develop various subtypes and to progress malignant stages of cancer was well documented [2, 3]. Extensive studies over the last few decades revealed that most cancers are exacerbated by dysregulation in several transcription factors (TFs) including nuclear factor-κB (NF-κB), signal transducers and activators of transcription (STATs), core-binding factor family TFs, ETS family TFs, runt-related TFs (RUNX1-RUNX3), and nuclear receptors (NRs) [4,5,6,7]. NRs have consistently been at the center of cancer research, where they have been shown to function as critical disease regulators. Several tumor types display a diverse set of NRs, whose interactions give different pathways for disease development and possibly exploitable therapeutic interventions [8,9,10,11,12,13]. Rapid advancement in genomic technologies has enabled more in-depth examination of the genome-wide impact of NRs on gene regulation emphasizing the vital role of coactivators and context [8, 14]. Therefore, NRs serve as biomarkers for tumor sub-classification and as therapeutic targets for developing novel drugs [8, 15]. To date, small molecules that bind to particular NRs have been one of the most effective and successful ways of targeting TFs in cancer [16, 17]. Drugs that directly influence the activity of the androgen receptor (AR), estrogen receptor (ER), glucocorticoid receptor (GR), and retinoic acid receptor (RAR) are currently employed to treat prostate cancer (PC), breast cancer (BC), acute lymphoblastic leukemia (ALL), and acute promyelocytic leukemia (APL), respectively [17,18,19]. The Food and Drug Administration (FDA) has approved more than ten chemotherapeutic drugs that target NRs for cancer treatment [16, 17]. However, few of these medications in log-term usage have shown inevitable adverse effects including deep vein thrombosis, pulmonary embolism, hypertension, severe hot flushes, epilepsy, depression, insomnia, cataracts, vaginal dryness, weight gain, fatigue, insomnia, seizures, and irritability affecting quality of life and survival of patients [17, 20]. As a result, establishing effective strategies to modify and reverse the neoplastic environment and significantly improve patient survival is imperative and is a key element of current pharmacological research. Interestingly, advanced in vitro, in vivo, ex vivo, and clinical studies have illustrated that natural compounds are safe, less toxic, economical, efficient multitargeting agents and have been a massive success for the treatment of various malignancies [21,22,23]. Natural products have a wide range of chemical scaffolds and have evolved to perform a variety of biological activities, giving them considerable drug-likeliness and making them a good source for finding novel drug leads [24,25,26]. These products accounted for approximately 25% of newly approved anti-cancer drugs during the period between 1981 and 2019 [27,28,29]. Concurrently, a plethora of compounds with anti-cancer potentials and/or distinct benefits in probing treatment modalities for neoplasms has been identified [30, 31]. Enormous research has established that NRs play a pivotal role in a wide range of metabolic and inflammatory illnesses, including diabetes, dyslipidemia, cirrhosis, fibrosis, and cancer. Numerous naturally occurring substances operate as NR ligands, controlling carbohydrate and lipid metabolism by modulating NR activity. Recent research has focused on potential NR modulating natural compounds derived from traditionally used medicinal plants or dietary sources for the prevention and treatment of various malignancies [8,9,10,11]. In this review, we provide an overview of natural compounds including phytochemicals, animal-derived agents, metabolites, and microbially derived substances that possess anti-cancer activities by targeting NRs. We have also presented the summary of ongoing clinical trials and patents on natural drugs that target NRs in cancer. Moreover, we have discussed the advantages and limitations of using natural compounds and highlighted future research regarding their potential as NR targets for the treatment of neoplasm.

2 NR superfamily and their mechanism of action

NRs are a family of ligand-dependent transcription factors that influence diverse physiological processes including embryonic development, cell growth, differentiation, systemic and cellular metabolism, homeostasis, immunity, and reproduction [16, 32,33,34,35,36,37]. In humans, a total of 48 members of this superfamily have been discovered to date [32]. Unlike other transcription factors, NRs directly bind to their lipophilic ligands such as steroid hormones and bile acids [38, 39]. NRs are divided into three distinct groups based on their interaction with the type of ligand as endocrine NRs, adopted NRs, and orphan NRs (Fig. 1A, B). Members of endocrine NRs are steroid hormone receptors including androgen (AR), estrogen (ER), glucocorticoid (GR), mineralocorticoid (MR), and progesterone (PR) receptors [32, 40]. These receptors bind to DNA as homodimers to initiate target gene expression, and their ligands indeed are synthesized in the endocrine glands which are regulated by the hypothalamic-pituitary axis [41]. The circulating steroid hormones display a high affinity to their respective NRs with a dissociation constant of 0.01 to 10 nM [41]. This class of receptor systems controls a wide range of physiological processes including metabolism, sexual dimorphism, reproduction, and electrolyte balance [41]. Adopted NRs are those that were previously classified as orphans but were subsequently adopted as NRs once the physiological ligand was characterized and functions as heterodimers with the retinoid X receptor (RXR) [40]. The members of this group include receptors for bile acids—farnesoid X receptor (FXR); fatty acids—peroxisome proliferator–activated receptors (PPARs); oxysterols—liver X receptors (LXR); xenobiotic receptors—steroid xenobiotic receptor or pregnane X receptor (SXR/PXR); and constitutive androstane receptor (CAR). These receptors possess lower affinities to their lipid ligands with the dissociation constant of > 1 to 10 μM [40]. A feedforward metabolic cascade is activated when a cognate ligand binds to each of these receptors, maintaining lipid homeostasis by regulating the transcription of genes involved in lipid metabolism, transport, storage, and clearance [40]. In addition to these adopted NRs, four RXR heterodimer receptors that do not fit precisely into either paradigm include ecdysone, retinoic acid receptor (RAR), thyroid hormone receptor (TR), and vitamin D receptor (VDR) [40, 42,43,44,45]. These receptors regulate morphogenesis, development, metabolism, and homeostasis [40, 41]. The third paradigm is represented by the large number of orphan NR members whose ligands, targets, and physiological functions are not well-known. Orphan NRs include photoreceptor-specific nuclear receptor (PNR/NR2E3), small heterodimer partner (SHP/NR0B2), steroidogenic factor-1 (SF-1/NR5A1), liver receptor homologue-1 (LRH-1/NR5A2), dosage-sensitive sex reversal, adrenal hypoplasia congenita critical region on the X chromosome gene 1 (DAX-1/NR0B1), tailless (TLX/NR2E1), germ cell nuclear factor (GCNF/NR6A1), RAR-related orphan receptor alpha (RORA/RORα/NR1F1), RAR-related orphan receptor beta (RORB/RORβ/NR1F2), RAR-related orphan receptor gamma (RORC/RORγ/NR1F3), estrogen-related receptor alpha (ERRα/ESRRA/NR3B1), estrogen-related receptor beta (ERRβ/ESRRB/NR3B2), estrogen-related receptor gamma (ERRγ/ESRRG/NR3B3), Rev-ErbA alpha (Rev-Erbα/NR1D1), Rev-ErbB beta (Rev-Erbβ/NR1D2), testicular receptor 2 (TR2/NR2C1), testicular receptor 4 (TR4/NR2C2), hepatocyte nuclear 4 (HNF4A/NR2A21), the chicken ovalbumin upstream promoter transcription factor I (COUP-TFI/COUPTF1/NR2F1), the chicken ovalbumin upstream promoter transcription factor II (COUP-TFII/COUPTFB/NR2F2), nerve growth factor–induced clone B (NGFIB/NUR77/NR4A1), Nur-related factor 1 (NURR1/NR4A2), and neuron-derived orphan receptor 1 (NOR1/NR4A3) [46]. The physiological functions of NRs are summarized in Fig. 2.

Fig. 1

Classification of nuclear receptors and their physiological expression. A NRs are classified into endocrine receptors, adopted receptors, and orphan receptors based on whether their ligands and functions are known or unknown. The NRs along with their known physiological ligands have been shown. B NRs are widely expressed in almost all tissues. The predominantly expressed NRs in various organs are listed. The NRs in green color indicate tumor-inhibiting properties, red indicates tumor-promoting, and blue indicates dual nature. The figure was created in BioRender.com

Fig. 2

Molecular insight into physiological functions of NRs. The figure was created in BioRender.com

The structural arrangement of members of the NR superfamily has been remarkably evolutionarily conserved consisting of four major domains—the N-terminal domain (A/B region) activator function 1 region (AF1), deoxyribonucleic acid (DNA)–binding domain (DBD, C region) which possesses two zinc finger motifs that confer specificity for response elements binding, a hinge region (D) connecting DBD to ligand-binding domain (LBD, E/F region), and a ligand-dependent activator function 2 region (AF2) that interacts with coactivators [47, 48]. NRs activate the transcription of their target genes by directly binding to response elements via the DBD domain [47,48,49]. Ligands allosterically govern the NR interaction with the coactivator or corepressor proteins by affecting either folding or dislodging the C-terminal helix (H12) in the AF2 domain [47, 48, 50]. Interaction with the coactivators facilitates the recruitment of transcriptosomes and chromatin remodeling [47, 48]. Conversely, the recently deduced structure of full-length AR by Yu et al. provided evidence that a coregulator protein can bind to AR independently of the AF2 region [51]. Whether AR is an exception or this is the rule for other NRs remains to be revealed. Genomic studies have revealed that NRs bind to the 5′-RGKTCA-3′ region which is organized as direct repeats with a variable-length spacer of 0–5 bp (DR0–DR5) [48, 52,53,54]. Studies on NR interaction with response elements using protein binding microarray have shown that the length of DR spacing is a key determinant of the DNA-binding specificity of NRs. For instance, PPAR/RXR prefers binding to DR1, whereas LXR/RXR prefers DR4. Recently, domain mutation followed by protein microarray analysis demonstrated that NR specificity to response elements does not solely depend on the DR spacing length; instead, it is the activity of the binding site that confers the specificity [54]. This study also demonstrated that all the type II NR heterodimers bind to DNA through half-site mode on both full- and half-sites which is a classic DNA-based allostery [54].

Considering the variety of regulatory strata that appear to tune receptor function, it is indeed easy to comprehend how the amazing context-dependent of NR transcriptional regulation would be jeopardized without the multitude of activators, repressors, and coregulators discovered to date. A plethora of studies demonstrated that coactivators, and/or corepressors, and/or regulators are primed for recruitment by NRs in response to appropriate triggers. The rapid development of molecular biology techniques and cloning of mammalian cDNAs encoding steroid receptor coactivator 1 (SRC-1)/nuclear receptor coactivator 1 (NCoA-1), glutamate receptor interacting protein 1 (GRIP-1)/transcriptional mediators/intermediatory factor 2 (TIF2)/steroid receptor coactivator 2 (SRC-2), and p300/CBP interacting protein (p/CIP)/RAC3/ACTR/AIB-1/TRAM-1/SRC-3 enabled to identify them as a family of ligand-recruited NR coactivators, SRC/p160 family [55,56,57,58,59,60,61,62,63]. The acetyltransferases CREB-binding protein (CBP) and p300; methylases coactivator-associated arginine methyltransferase 1 (CARM-1) and protein arginine methyltransferase 1 (PRMT-1); switch/sucrose non-fermentable (SWI/SNF) complex; serum resistance–associated protein (SRA); triiodothyronine captor auxiliary protein (TRAP)/vitamin D receptor–interacting protein (DRIP) complex; transcriptional machinery proteins — TATA-box binding protein (TBP), TBP-associated factors (TAFs), and ubiquitin ligase E6–associated protein (E6-AP) are the additional proteins that met some or all the experimental criteria to be defined as NR coactivators [57, 62, 64,65,66,67,68,69,70,71,72,73]. A helical LXXLL motif or NR box is a common structural characteristic of NR coactivators [74]. In addition, various families of coactivators share several functional features, for instance, acetyltransferase activity is common among CBP, p300/CBP-associated factor (PCAF), and members of the SRC family [63, 75,76,77]. Corepressors of NRs (NCoR) and silencing mediators of thyroid and retinoid receptors (SMRT) and repressor of estrogen activity (REA) are analogous to coactivators and are recruited by NRs in the presence or absence of ligands or by the antagonists such as tamoxifen and RU486 [62, 78, 79]. Moreover, amphipathic helical peptides known as “CoRNR boxes” are exploited by transcriptionally inert NRs to recognize corepressors [80]. Corepressors and coactivators are functionally similar, in addition to their structural similarities. Furthermore, coactivators of NRs are subjected to modulation by selective repressor molecules such as RIP140 [81, 82]. Perhaps more crucially, several specific posttranslational changes have a great impact on how NRs, their coregulator complexes, and their cognate gene networks function. Phosphorylation of NRs aid in compartmentalization and methylation aid in coregulator recruitment, while ubiquitination reduces the half-life [, 62, 83].

3 NRs in tumorigenesis and anti-cancer therapeutics

The importance of NRs in promoting the genesis and progression of cancer has been well recognized [16, 17, 84, 85]. Their roles in tumorigenesis are complex and paradoxical. The hormone receptors including ER, PR, and AR are required for homeostasis and contribute to tumorigenesis when aberrantly triggered in various cancer models. These receptors exert their effects via classical signaling milieu such as phosphatidylinositol 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), Notch, and Ras/mitogen-activated protein kinase (MAPK) pathways [9,10,11, 84, 85] (Figs. 3 and 4). Likewise, other nuclear receptors, such as GR and RARs, as well as adopted nuclear receptors, such as PPAR, RXR, ERRs, and LXR have been known to play a pivotal role in tumor progression, including the regulation of proliferative signaling, initiation of metastasis, interruption of apoptotic and autophagy signaling, angiogenesis, and metabolic reprogramming [9,10,11, 86,87,88,89]. A growing body of evidence shows that nuclear receptors fine-tune the effector functions of immune cells by regulating immunometabolic events [90, 91]. Indeed, several NRs are classified as metabolic receptors, including FXR, LXRs, PPARs, and PXR. These receptors were shown to regulate NLRP3-mediated inflammasome activation in various cancer models such as breast, colon, leukemia, and lung [90, 91]. In addition, NRs have been demonstrated to modulate drug resistance via altering multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP) expression [92,93,94,95]. For example, PXR and the CAR were shown to interact with the MDR1 promoter and activate transcription [96,97,98]. Moreover, the BCRP promoter possesses response elements for both ER and PPARγ, indicating that NRs are involved in BCRP expression regulation [99, 100]. Interestingly, Geick et al. discovered a distal enhancer region (at about − 7.8 to − 8 kilobase pairs) from the transcriptional start site (TSS) of the MDR1 gene promoter that governs rifampicin-induced MDR1 expression in LS174T colon cancer cells. This study also validated that PXR/RXR binds to 3 DR4 (I, II, and III) and an ER6/DR4 complex by using an electrophoretic mobility shift assay (EMSA) (III). In addition, mutational investigations revealed that DR4(I) is required for rifampicin-mediated MDR1 induction [97]. Subsequently, Burk et al. demonstrated that MDR1 is additionally controlled by CAR, through the DR4(I) and, to a lesser extent, the ER6/DR. Both DR4(I) and DR4(II) are required for the maximal induction of MDR1 by CAR [101]. In addition, PXR agonists including rifampicin, St. John’s Wort, and carbamazepine can increase intestinal MDR1 expression while lowering the bioavailability and plasma concentrations of digoxin, talinolol, and fexofenadine that transported through MDR1 [96, 97]. Furthermore, SR12813 treatment stimulated PXR in the PC3 prostate cancer cell line and induced MDR1 expression and resistance to the anti-cancer medicines paclitaxel and vinblastine. PXR downregulation using siRNA in the endometrial cancer cell line HEC-1 reduced MDR1 expression and sensitized to paclitaxel and cisplatin [96]. Furthermore, elevated expression of RORC has been shown to promote cisplatin-induced apoptosis in bladder cancer both in vitro and in vivo through programmed cell death ligand 1 (PDL-1)/integrin subunit beta 6 (ITGB6)/signal transducer and activator of transcription factor 3 (STAT3) pathway [102]. More recently, Hu et al. demonstrated that suppression of TR4 by bexarotene resulted in increased sensitivity to docetaxel in prostatic cancer cell lines [103].

Fig. 3

Involvement of NRs in the regulation of cancer cell hallmarks. NRs regulate a wide range of cellular and molecular processes. The cancer cell hallmarks and the involvement of NRs in each process have been shown. The figure was created in BioRender.com

Fig. 4

Mechanism action of natural compounds through targeting NRs. NRs act upon several different pathways including NF-κB, STAT3, Akt, ERK, and Wnt signaling pathways to promote or inhibit cellular processes such as cell proliferation, cell cycle, and gene expression. The figure details the mechanism of action of NRs on different pathways and the role of natural compounds. The figure was created in BioRender.com

Innovative recent studies are providing enthralling support that targeting NRs by various approaches is a promising strategy against the progression and outcome of neoplastic diseases. Many anti-cancer drugs approved by FDA have been shown to target nuclear receptors (Table 1) [104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128]. However, these drugs have shown severe to moderate adverse side effects. This demands the screening of novel therapeutic agents that target NRs which possess low or no side effects and high efficacy.

Table 1 FDA-approved drugs targeting NR and their adverse effects

4 Natural compounds as NR targets in cancer

Considering ligands play a critical role in modifying NR function, NR agonists and antagonists have been proposed for pharmacological development. Research over the past several years has showcased the cancer chemopreventive and therapeutic potential of natural products and their derivatives against various cancers [24,25,26, 129,130,131,132,133,134,135,136,137,138]. Biochemical, structural, and pharmacological screening and characterizations of natural product libraries have successfully discovered several unique compounds that modulate NRs [139]. A wide range of natural compounds from different sources including plants, animals, and microbially derived substances have been reported to possess anti-cancer activities by modulating NR expression [140,141,142,143]. In this section, we provide a detailed overview of these NR-targeting natural compounds and their anti-cancer mechanism with an emphasis on their therapeutic potential. The details about the natural compounds targeting nuclear receptors in various cancers are summarized in Table 2.

Table 2 The natural compounds that target NR and their anti-cancer effects

5 Phytochemicals as NR modulators

Over the past several decades, numerous phytochemicals including alkaloids, carotenoids, coumarins, curcuminoids, flavonoids, indole derivatives, lignans, and terpenoids have been reported as anti-neoplastic agents by exhibiting agonistic or antagonistic properties against human NRs. The next section details some of the important phytochemicals that modulate the expression of NR and possesse anti-cancer properties. Figure 5 illustrates the various phytochemicals and their target NRs leading to reduced cancer hallmarks.

Fig. 5

Phytochemicals that target various NRs lead to reduced hallmarks of cancer cells. The extracts, juices, and emulsions of plants and the phytochemicals including alkaloids, carotenoids, curcuminoids, dietary and non-dietary terpenoids, isoflavones, and isoprenols have been shown to possess anti-cancer and anti-inflammatory activities through the modulation of various NRs. The figure was created in BioRender

5.1 Alkaloids

Alkaloids are a broad collection of chemicals that possess cyclic structures with at least one basic nitrogen atom. These compounds are primarily found in plants belonging to the Leguminosae, Loganiaceae, Menispermaceae, Ranunculaceae, and Papaveraceae families. Numerous alkaloids are well-known as potent chemotherapeutic drugs, including berberine, camptothecin, evodiamine, matrine, vincristine, piperine, sanguinarine, tetrandrine, and vinblastine [144,145,146,147]. Alkaloids have also been shown to inhibit cancer progression through the modulation of NRs. For instance, treatment of KM12C colon cancer cells with berberine, a small molecule isoquinoline alkaloid isolated from rhizomes of Coptis chinensis and Hydrastis canadensis, at 25 μM attenuated proliferation and cell cycle by binding and activating RXRα, suppressing β-catenin signaling, and enhancing the expression of target genes including ATP binding cassette subfamily A member 1 (ABCA1), forkhead box O3 (FOXO3A), apolipoprotein E (APOE), cyclooxygenase 2 (COX2), and proliferating cell nuclear antigen (PCNA) [148, 149]. Similarly, another natural alkaloid, caffeine, found in a variety of plants including cocoa beans, coffee beans, cola nuts, and tea leaves, has been shown to limit cell proliferation, eliminate chemical or radiation-induced impediments in normal cell cycle, increase the cytotoxicity to radiation and anti-cancer drugs, and reduce ultraviolet B (UVB) radiation–induced malignant transformation [150,151,152,153,154,155,156]. Recently, Faudone et al. demonstrated that caffeine (30 μM) modulates orphan nuclear receptor TLX activity in T98G glioblastoma cell line. This study also showed that the derepression of TLX by caffeine diminished FXR, NURR1, RARα, and RXRα [157]. Another compound, capsaicin (N-vanillyl-8-methyl-nonenamide), a spicy component of pepper, preferentially promotes apoptosis in specific cancer cells and has a putative role in cancer chemoprevention [158]. In another study, Kim and colleagues demonstrated that capsaicin-induced PPARγ both at mRNA and protein levels led to apoptotic cell death of HT-29 cells and this effect was abrogated by the addition of PPARγ inhibitor [159]. In addition, capsaicin at 200 μM has been shown to enhance transient receptor potential cation channel subfamily V member 1 (TRPV1), adenosine mono phosphate (AMP)–activated protein kinase (AMPK), calcium/calmodulin-dependent kinase kinase beta (CaMKKβ), phospho-sterol regulatory element binding protein 1c (p-SREBP1c), p62, PPARα, PPARγ, and autophagy and reduce phosphorylation of Akt, mTOR, and lipid accumulation in HepG2 cells [160]. Likewise, a major dietary alkaloid found in the extracts of Piper longum and P. nigrum, piperine, has been earlier attributed to anti-cancer, anti-inflammatory, anti-microbial, chemopreventive, and immunosuppressive activities and was also shown to modulate NRs [161,162,163]. It was shown that piperine of 100 μM concentration elevated miR-181c-3p levels and suppressed leptin-induced proliferation, colony formation, and migration of breast cancer cells via PPARα inhibition [163].

5.2 Carotenoids

Carotenoids are membrane-stabilizing chemicals recruited as photoprotective pigments during photosynthesis. According to their chemical structure, carotenoids are classified as isoprenoid polyenes, which are lipid-soluble, yellowish-orange pigments and are biosynthesized by algae, plants, and certain microbes [164, 165]. Carotenoids including astaxanthin, β-carotene, β-cryptoxanthin, crocin, fucoxanthin, lutein, and lycopene are the most common plant pigments that play key roles in the prevention and treatment of several diseases, including cancer [166]. Zhang et al. explored the anti-proliferative activities of four different carotenoids β-carotene, astaxanthin, capsanthin, and bixin on K652 leukemia cancer cells. It was observed that these carotenoids attenuated cancer cell growth and cell cycle by upregulating PPARγ in a dose-dependent manner ranging from 0.5 to 50 μM. This study also showed the upregulation of p21 and nuclear factor erythroid–related factor 2 (NRF2), and inhibition of cyclin D1 expression was PPARγ dependent [167]. In another study, Liu and coworkers demonstrated that fucoxanthin extracted from Undaria pinnatifida inhibited the proliferation and expression of cytochrome P450 3A4 (CYP3A4) and MDR1 in colon and hepatocarcinoma cell lines by blocking the interaction of PXR with SRC1 [168]. Moreover, this compound was shown to induce apoptosis and enhance the anti-proliferative effect of troglitazone in colon cancer cell lines by activating PPARγ [169]. Another carotenoid, β-cryptoxanthin, purified from Citrus unshiu has been shown to arrest the cell cycle and reduce proliferation by upregulating RARβ in lung cancer cells [170]. In addition, β-cryptoxanthin hampered nicotine-induced lung cancers in male A/J mice by transactivating RARβ resulting in decreased interleukin 6 (IL-6), increased sirtuin 1 (SIRT1), and survival probability [171]. Furthermore, apo-10′-lycopene, a lycopene derivative, has been shown to reduce migration, invasion, and angiogenesis dose-dependently (2.5–40 μM) in the liver and lung cancer in vitro models through the activation of PPARγ [172].

5.3 Polyphenols

Polyphenols are substances with one or more hydroxyl group(s) linked to at least one aromatic ring. They are the broad collection of secondary metabolites found in plants that range in size from small molecules to highly polymerized substances. They are widely distributed in plant-based foods and beverages including fruits, nuts, soy, spices, tea, vegetables, and wine [173]. Natural polyphenols are categorized into five types based on their chemical structures: flavonoids, phenolic acids, lignans, stilbenes, and other polyphenols [174, 175]. A plethora of research has documented the anti-cancer properties of polyphenols. Anthocyanins from blueberries, curcuminoids from turmeric, epigallocatechin gallate (EGCG) from green tea, isoflavones from soy, and resveratrol from red wine are a few noteworthy examples [175,176,177,178,179,180]. This section summarizes the NR-targeting activities of different polyphenols in various cancers.

5.3.1 Acetylshikonin

Acetylshikonin is a physiologically active biochemical commonly obtained from the roots of Lithospermum erythrorhizon, with anti-tumor and anti-inflammatory properties [181, 182]. Several reports have demonstrated that acetylshikonin induces apoptosis and endoplasmic reticulum stress through the activation and cytoplasmic localization of NUR77 in cervical, liver, and lung cancer cells [183, 184].

5.3.2 Artemisinin

It is a bioactive sesquiterpene lactone isolated initially from the Artemisia annua and is a potent anti-malarial drug. Artemisinin has long been recognized for its anti-cancer activity due to its preference for cytotoxic effects in cancer cells than normal cells [185]. Studies have reported that artemisinin exerts its effects through modulating NF-κB, vascular endothelia growth factor (VEGF), MAPK, hypoxia-inducible factor 1 alpha (HIF-1α), survivin, and Wnt signaling [185]. It has also been shown to inhibit AR activities and enhance AR binding to MDM2 leading to reduced proliferation of prostate cancer cells [186]. Artesunate, a derivative of Artemisia annua, and artemisinin derivatives also showed the suppression of prostate cancer cell growth through the degradation of AR [187, 188]. In addition, another derivative of artemisinin, dihydroartemisinin has been demonstrated to induce cell death and inhibit migration of colon cancer cells via the induction of PPARγ [189].

5.3.3 Auraptene

Auraptene is a monoterpene isolated from Citrus fruits. Auraptene is known to possess anti-bacterial, anti-diabetic, anti-fungal, anti-genotoxic, anti-inflammatory, and anti-protozoal effects [190]. It exerts anti-cancer effects by modulating the expression of matrix metalloproteinases (MMPs), VEGF receptor 1 (VEGFR1), VEGF receptor 2 (VEGFR2), IL-6, IL-2, STAT3, NF-κB, and PPARα in various cancers including breast, cervical, colon, liver, and ovarian cancer cells [191,192,193,194].

5.3.4 Baicalein

Baicalein is a major active ingredient extracted from the root of Scutellariae radix. Its anti-tumor actions are mediated by numerous molecular pathways, including blocking multiple cyclins or cyclin-dependent kinases (CDKs) that control the cell cycle, scavenging free radicals, and limiting MAPK, Akt, and mTOR activities [195, 196]. Baicalein also has been demonstrated to suppress the growth of meyeloma cells through the activation of PPARβ [197]. Baicalein, chrysin, and galangin derived from garlic have been shown to retard the growth of liver cancer cells through the upregulation of CAR [198]. In addition, baicalein attenuated cell cycle arrest in prostate cancer cells by alleviating AR activity [199].

5.3.5 N-butylidenephthalide

N-butylidenephthalide, a compound derived from Angelica sinensis, has been shown to suppress the growth of several human cancer cell lines, including breast, brain, lung, and liver cancer cells [200,201,202,203,204]. In liver cancer cells, n-butylidenephthalide reduced cell proliferation via activating NUR77 [204]. In another study, Lin et al. examined that n-butylidenephthalide impeded cell proliferation and induced cell death through the activation of NUR1 and NUR77 in both in vitro and in vivo models of glioblastoma [205].

5.3.6 Celastrol

A polyphenol, celastrol, is a quinine methide triterpenoid isolated from the Tripterygium wilfordii and has evolved as a potential anti-cancer agent during the last few years [206,207,208]. Celastrol inhibited constitutively active STAT3 and liver cancer cell migration in pre-clinical studies [209]. Addition of celastrol inhibited expression of STAT3, Akt, p38, p65, c-Jun N-terminal kinase (JNK), and IL-6 through the suppression of peptide-prolyl cis–trans isomerase NIMA-interacting 1 (Pin1) resulting in reduced proliferation, migration, and stemness of ovarian cancer cells [210]. Another study showed celastrol prevents prostate cancer cell growth both in vitro and in vivo by targeting AR to proteasomal degradation [211]. Recently, Hu et al. investigated the role of celastrol on liver cancer cells and found that celastrol reduced inflammation by fostering mitochondrial ubiquitination and autophagy through the activation of NUR77 [212].

5.3.7 Cryptotanshinone

Cryptotanshinone, a principal tanshinone extracted from Salvia miltiorrhiza roots, is commonly used in herbal medicine to treat diabetes, cardiovascular diseases, cancer, chronic renal failure, hepatitis, and menstrual disorders [213, 214]. It is shown to suppress the castration-resistant prostate cancer cells both in vitro and in vivo by reducing the transactivation of AR and by profound inhibition of AR binding to lysine-specific demethylase 1 (LSD1) [215, 216].

5.3.8 Curcumin

It is a naturally occurring polyphenol found in the rhizomes of Curcuma longa and has piqued the interest of scientists across the world due to its various biological properties including anti-oxidant, anti-microbial, anti-viral, anti-inflammatory, and anti-cancer effects [217,218,219,220]. Curcumin has been shown to exert anti-cancer effects by modulating several pathways including NF-κB signaling, Akt/mTOR signaling, STAT signaling, epidermal growth factor receptor (EGFR) signaling, interleukin pathways, cyclins, CDKs, MMPs, and NRs [221, 222]. Prakobwong et al. illustrated that curcumin mediates anti-proliferative and apoptotic effects through the inhibition of NF-κB nuclear translocation, STAT3 phosphorylation (Y703 and Y705), Akt phosphorylation, and activation of PPARγ at the concentration of 50 μM in KKU100, KKU-M156, and KKU-M214 cholangiocarcinoma cell lines [223]. This study also showed that curcumin downregulated B-cell lymphoma 2 (Bcl-2), X-linked inhibitor of apoptosis (XIAP), cellular FLICE inhibitory protein (c-FLIP), a cellular inhibitor of apoptosis protein 1 (cIAP-1), a cellular inhibitor of apoptosis protein 2 (c-IAP-2), survivin, cyclin D1, c-Myc, and upregulated death receptors DR4 and DR5 resulting in enhanced apoptosis of biliary cancer in vitro [223]. Moreover, curcumin has been revealed to induce LXRα and FXR expression in hepatoma cell lines HepG2 and Huh7 leading to reduced inflammation, cell viability, and enhanced expression of ATP-binding cassette subfamily G member 1 (ABCG1), cytochrome P450 family 7 subfamily A member 1 (CYP7A1), cytochrome P450 family 8 subfamily B member 1 (CYP8B1), organic anion transporting polypeptide 1A1 (OATP1A1), ileal bile acid transporter gene (IBAT), and organic solute transporter beta subunit (OSTβ) [224, 225]. In another study, Jiang et al. showed that curcumin reactivated silenced RARβ by reducing promoter DNA methylation in lung cancer in vitro and in vivo resulting in reduced tumor growth [226]. In two independent studies, curcumin was shown to activate PPARγ, VDR, RAR, and RXR expressions in various colon cancer cell lines causing increased AMPK and decreased COX2 expression [227, 228]. Besides, curcumin activated VDR resulting in the upregulation of CYP3A4, CYP24, p21, and TRPV6 and enhanced chemoprevention in Caco-2 cells [229]. In Moser cells (human colon cancer–derived cell line), curcumin induced cell cycle arrest at the G2/M phase, suppressed cell survival/proliferation, and reduced EGFR phosphorylation by activating PPARγ [230]. In various breast cancer in vitro models, curcumin showed apoptotic effects via upregulating PPARγ, RARβ, and RARγ and downregulating PPARβ leading to increased cleaved-PARP, cleaved caspase-9 levels and reduced COX2, phospho-extracellular signal-regulated kinase (p-ERK), p38, VEGF, pyruvate dehydrogenase kinase 1 (PDK1), and p65 [227, 231, 232]. In another study, curcumin (12 μM) treatment along with docosahexaenoic acid (18 μM) showed synergistic effects on inhibiting apoptosis and metastasis in vitro through PPARγ activation in breast cancer cells [233].

5.3.9 Ellagic acid

Ellagic acid is a plant-derived polyphenol abundant in pomegranates, raspberries, and walnuts [234]. In experimental cancer models, ellagic acid was reported to decrease the incidence of chemically induced colon, lung, mammary, oral, and intestinal tumors [235,236,237,238,239]. Furthermore, Munagala and coworkers demonstrated that this compound reverses the micro-RNA signatures including miR-182, miR-375, miR-183, miR-122, miR-127, and miR-206 and modulates the expression of cyclin D1 (CCND1), cyclin G1 (CCNG1), Bcl-w, FOXO1, FOXO3A, and Ras-related dexamethasone-induced 1 (RASD1) in estrogen-mediated mammary tumors [239]. In addition, ellagic acid derived from pomegranates has been found to inhibit AR expression in prostate cancer cells [240].

5.3.10 Embelin

Embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone) is a major active component isolated from the fruits of Embelia ribes, and it has been studied for the treatment of a wide range of cancers [241, 242]. Dai and co-workers demonstrated that embelin impedes the cell proliferation and tumor growth of colon cancer cells via the reduction of CCND1, PCNA, survivin, and COX2 in both in vitro and in vivo colon cancer models. This study also showed that embelin exerts its anti-cancer mechanism through the activation of PPARγ and failed to induce cancer cell death in PPARγ^−/− mice [85].

5.3.11 Emodin

Emodin (1,2,8-trihydroxy-6-methylanthraquinone), a bioactive chemical isolated from Rheum palmatum, is more effective than genistein and curcumin on prostate cancer cells [243, 244]. It has been demonstrated to be a potent AR antagonist and downregulates prostate cancer cell proliferation [245]. Additionally, emodin has been revealed to inhibit cell growth and division of liver cancer cells through the activation of FXR and modulating gene expression of such as Cdc25c, cyclin B, Chk2, CDK2, p27, p21, CDK1, palmdelphin (PALMD), insulin-like growth factor binding protein 3 (IGFBP3), thioredoxin-interacting protein (TXNIP), Chac cation transport regulator-like 1 (CHAC1), CYP1B1, CYP1A1, TCDD-inducible poly (ADP-ribose) polymerase (TIPARP), growth differentiation factor 15 (GDF15), serpin peptidase inhibitor clade E member 1 (SERPINE1), son of sevenless homolog 1 (SOS1), RASD1, solute carrier family 7A member 11 (SLC7A11), cysteine-rich angiogenic inducer 61 (CYR61), and muscle RAS oncogene homolog (MRAS) [246].

5.3.12 Genistein

Genistein [5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one] is a predominant isoflavone found in soy and soy-based food products consumed by Asians daily. The principal molecular targets of genistein include Akt, Bax, Bcl-2, caspases, ERK, MAPK, NF-κB, and Wnt signaling pathway [247]. This phytochemical was shown to inhibit the prostate cancer cells by exerting an inhibitory effect on nuclear receptor AR at the physiological concentration [248]. It also induced prostate cancer cell death by activating ERβ [249]. Genistein-mediated reduction of cholesterol accumulation, an increase of apoptosis, and alleviation of prostate-specific antigen (PSA) levels were attributed to AR degradation in prostate cancer cells [250, 251]. Besides, genistein together with resveratrol was found to be the potent antagonist of AR in prostate cancer cells [252]. In addition, genistein treatment was shown to reduce hydrogen peroxide–induced oxidative stress and overexpression of Nrf2 in lung cancer hybrid cells through the activation of PPARγ [253]. Another study showed that genistein-induced reduction of AR resulted in induction of cleaved poly(ADP-ribose) polymerase (PARP), cleaved-caspase 3, and downregulation of ABI family member 3–binding protein (ABI3BP), A-kinase anchoring protein 12 (AKAP12), annexin A3 (ANXA3), amyloid beta precursor protein–binding family B ember 1–interacting protein (APBB1IP), bone morphogenic protein receptor type 1B (BMPR1B), F-box leucine–rich repeat protein 7 (FBXL7), gastrulation brain homeobox 2 (GBX2), general transcription factor IIA subunit 1 (GTF2A1), high mobility group AT hook 2 (HMGA2), muscleblind-like splicing regulator 1 (MBNL), MYB-binding protein 1A (MYBBP1A), neural EGFL-like 2 (NELL2), phosphofructokinase subunit M (PFKM), phosphoserine aminotransferase 1 (PSAT1), pseudouridine synthase 1 (PUS1), serum glucocorticoid regulated kinase 2 (SGK2), and T-box transcription factor 19 (TBX19) in ovarian cancer cells resistant to taxol [254]. Furthermore, it was shown that isoflavones genistein, formononetin, calycosin, daidzein, and biochanin A isolated from Astragalus membranaceus and Astragalus membranaceus activate both PPARα and PPARγ in HeLa cervical cancer cells [255].

5.3.13 Guggulsterone

Guggulsterone is a sterol isolated from the gum resins of the Commiphora sp. tree and is widely used in Indian traditional medicine for the treatment of various diseases [131, 256,257,258]. Recently, guggulsterone has been proven to be a potential anti-tumorigenic agent in several cancers such as head and neck, lymphoma, and pancreatic and prostate malignancies [259]. For example, guggulsterone has been shown to reduce cell viability and induce apoptosis in TE-3 and TE-12 esophageal cancer cells [260]. In addition, E- and Z-guggulsterone isomers at 40 μM concentration have been demonstrated to induce apoptosis through caspase 3 and PARP cascade, induce cell cycle arrest by upregulating p21, and reduce bladder cancer cell viability via inducing FXR activation [261]. Another study revealed that Z-guggulsterone attenuates bile acid–induced FXR expression and NF-κB signaling in in vitro models of gastric intestinal metaplasia [262]. In hepatocarcinoma cells, guggulsterone has been shown to lower cholesterol accumulation by inhibiting FXR, PPARα, PXR, and SHP expressions [263]. Furthermore, guggulsterone suppressed FXR expression dose-dependently which resulted in reduced cell viability, cell migration, and invasion of PANC-1 and MIA-PaCa2 cell lines [264]. In another study, guggulsterone combined with bexarotene reduced resistance to doxorubicin and induced apoptosis in breast cancer cells through the inhibition of FXR and RXR [265]. More recently, Tian et al. examined that Z-guggulsterone inhibited cell cycle progression of non-small cell lung cancer cells and hampered tumor growth in Lewis lung carcinoma xenografts in a dose and time-dependent manner. The mechanistic experiments demonstrated that Z-guggulsterone at a concentration of 40 μM mediated the upregulation of PD-L1 partly by inhibiting FXR in these cells [266].

5.3.14 Gypenoside XLIX

Gypenosides are the major components in Gynostemma pentaphyllum and have shown high anti-cancer efficacy in different experimental settings [267]. A clinical study conducted in 1993 revealed that Gynostemma pentaphyllum soup reduced cancer relapse rate and metastasis rate to 11.9% and 8.5% compared to 72.4% and 55.2% in the control group respectively in advanced metastatic cancer patients [268]. A plethora of studies has shown that gypenosides induce apoptosis of cancer cells by generating ROS and reducing mitochondrial membrane potential [269,270,271,272]. In line with these studies, Huang et al. illustrated that the gypenoside XLIX isolated from the Gynostemma pentaphyllum abolished the LPS-induced inflammation and reduced tissue factor in leukemia cells through the activation of PPARα [273].

5.3.15 Hesperidin

Hesperidin, also known as hesperetin 7-rutinoside, a flavonoid present naturally in citrus fruits, is recognized to have broad-spectrum applicability in the prevention and treatment of cancer [274, 275]. Hesperidin is shown to induce cell cycle arrest by downregulating cyclin D1 and upregulating wild-type p53 levels. It is also known to stimulate the autophagy pathway through Aurora-A-mediated PI3K/Akt/glycogen synthase kinase 3 beta (GSK-3β) pathway in the colon cancer model [274, 276, 277]. Moreover, hesperidin is shown to attenuate cell cycle, proliferation, ATP synthesis, and mitochondrial DNA replication synergistically either with piperine and bee venom or with chlorogenic acid in breast cancer in vitro models through the inhibition of ERα [278, 279].

5.3.16 Honokiol

Recent studies have enumerated the anti-angiogenic, anti-cancer, anti-inflammatory, and anti-oxidant mechanisms of another polyphenol, honokiol (3′,5-di-(2-propenyl)-1,1′-biphenyl-2,4′-diol), isolated from the bark of Magnolia spp. [280]. It has been shown to target multiple signaling pathways including NF-κB, STAT3, EGFR, and Akt/mTOR [281, 282]. Additionally, Jung and coworkers showed that honokiol induced apoptosis of glioblastoma cells by activating RXRβ [283].

5.3.17 Morusin

Morusin, a flavonoid isolated from the root bark of Morus australis and the branch of Ramulus mori, has been shown to exhibit cytotoxicity against breast cancer, cervical cancer, colorectal cancer, liver cancer, and prostate cancer [284,285,286,287,288]. Li et al. showed that the inclusion of 4 μg/mL and 6 μg/mL morusin enhanced the expression of PPARγ in MCF-7 and MDA-MB-231 cells in vitro and inhibited colony formation and induced apoptosis in these cells [289]. This study also demonstrated that treatment of mice with 5 mg/kg and 10 mg/kg body weight of this compound significantly increased the expression of PPARγ in tumor tissues and inhibited the further growth of tumors in nude mice bearing MCF-7 cells [289].

5.3.18 Resveratrol

Resveratrol (3,4′,5-trihydroxy-trans-stilbene), first purified from the roots of Veratrum album, has been proved as a potential anti-cancer agent by many studies during the last couple of decades [290,291,292]. Extensive preclinical and clinical studies have enumerated an inexhaustible list of therapeutic benefits of resveratrol ranging from boosting immunity, slowing aging, and anti-obesity effects, to alleviating the diseases such as diabetes, cancer, cardiovascular diseases, and neurodegenerative diseases [291]. In cancer cells, resveratrol has been shown to regulate several pathways including suppression of STAT3, Akt, HIF1α, MAPK, β-catenin, TGF-β, SMAD, Snail, IKK, FOXO3A, and NF-κB [291]. Resveratrol has been shown to inhibit cell proliferation and cell division in cancer cells through the activation of PPARγ in oral cancer cells [293]. In addition, Ulrich et al. demonstrated that resveratrol ameliorates spermine/spermidine acetyltransferase, cell growth, and induces PPARγ coactivator 1 alpha (PGC-1α), SIRT1, and p-38 in HCT116 and CaCo-2 cells through the activation of PPARγ [294]. In the anaplastic thyroid cancer cells, THJ-11 T, THJ-16 T, and THJ-21 T, resveratrol induced cell cycle arrest and apoptosis via the induction of RARβ and reduction of PPARβ [295].

5.3.19 Withaferin A

Withaferin A is a steroidal lactone purified from the leaves of Withania somnifera. It is a well-known phytochemical which has significant anti-inflammatory, pro-apoptotic, anti-angiogenic, anti-invasive, and anti-metastatic properties [296]. The direct cellular targets of withaferin A include cytoskeletal and structural remodeling proteins such as vimentin and desmin, transcription factors such as NF-κB and heat shock transcription factor 1 (HSF1), and kinases such as MAPK, Akt, JNK, ERK, and p38 [296, 297]. Recently, Shiragannavar and co-workers found that withaferin A (2.5 μM) inhibits hallmarks of hepatic neoplastic cells including proliferation, migration, and invasion by activating LXRα expression [298]. Furthermore, this study showed that treatment of HepG2 cells with withaferin A enhances the expression of LXRα targets ABCA1 and ABCG1. Withaferin A also inhibited angiogenesis by downregulating angiogenin, endothelin-1, macrophage migration inhibitory factor (MIF), plasminogen activator inhibitor-1 (PAI-1), monocyte chemoattractant protein 1 (MCP-1), intercellular adhesion molecule 1 (ICAM-1), serpin F1(PEDF), plasminogen activator urokinase (uPA), and platelet-derived growth factor (PDGF)-AA in an LXRα-dependent manner [298].

5.4 Other polyphenols

Several additional natural polyphenols have been shown to suppress various cancer hallmarks by targeting NRs. For instance, allyl isothiocyanate, found in Brassica species, was found to downregulate the expression of CYP3A4 and CYP2B6 by inhibiting PXR and CAR significantly at the concentration of 20 μM and 40 μM [299]. Another compound, asaronic acid, isolated from the purple perilla and its anti-inflammatory activities are confined to the PPARγ mediated activation of IL-4α, arginase-1, CD163, IL-10, p-STAT6, and TGF-β in a dose-dependent manner in J774.1 macrophages and THP-1 leukemia cells [300]. Also, atraric acid, isolated from the bark of Pygeum africanum and its derivatives, is shown to downregulate AR expression, thereby attenuating migration and invasion of prostate cancer cells [301, 302]. Another compound isolated from the bark of Pygeum africanum, N-butyl sulfonamide, was also revealed to reduce PSA and prostate cancer cell growth by inhibiting AR, PR, GR, and THRB [303]. Besides, a triterpene derived from Brucea species, bruceantin, was shown to attenuate cell growth and disrupt the interaction of AR with heat shock proteins such as HSP70, HSP90, and HSP40 [304, 305]. Moreover, a wedelolactone derivative, 3-butoxy-1,8,9-trihydroxy-6H-benzofuro[3,2-c]-benzopyran-6-one (BTB), belongs to the furanocoumarin family of compounds shown to regulate activation of ER [306]. This study also showed that the BTB retarded estrogen-induced growth of breast, endometrial, and ovarian cancer cells by reducing the expression of cyclin D1, E2F1, TERT, and c-Myc and inhibiting ERα and ERβ expression [306].

Recently, thirteen cucurbitanes isolated from the Momordica charantia plant were shown to possess inhibitory effects of Epstein-Barr virus antigen in Raji cells and reduced cell viability [307]. A compound isolated from the same extract, 3β,7β-dihydroxy-25-methoxycucurbita-5,23-diene-19-al (DMC), was revealed to induce PPARγ and ERα in breast cancer cells leading to increased expression of caspase-9, LC3-II, autophagosomes, and reduced cell proliferation [308]. In another study, 7-(O)-carboxymethyl daidzein, a soy isoflavone conjugated to N-t-boc-hexylenediamine, was examined for its anti-proliferative activities against thyroid carcinoma cells by activating ERα and ERβ [309]. Another study conducted by Ichikawa et al. reported that deoxyelephantopin, a sesquiterpene lactone obtained from leaf extract of Elephantopus carolinianus, exhibited inhibitory effects on NF-κB and modulated gene expression by repressing IKK [310, 311]. It was also demonstrated that deoxyelephantopin significantly inhibited cell cycle progression by upregulating PPARγ in HeLa cells [312]. Another sesquiterpene lactone, isoalantolactone, purified first from Inula helenium, has been shown to ameliorate the body fat and impede adipogenesis through the inhibition of NUR77 in MiaPaCa-2 cell lines [313]. In addition, farrerol (FA), a flavanone extracted from “Man-shan-hong,” a Chinese herbal medication (Rhododendron dauricum L.) inhibited the proliferation of SKOV3 cells and induced caspases through the activation of PPARγ [314, 315]. Recently, a natural cyclic AMP activator found in the roots of Coleus forskohlii, forskolin, has also been described to upregulate the expression of CYP3A4, NTCP, OATP2B1, and BSEP in liver cancer cells at a concentration of 50 μM and downregulated BCR/ABL expression at 40 μM concentration in leukemia cells [316, 317].

Another group of polyphenols, the dietary isoprenols, is known to perform multifunction such as cation channel regulation, suppression of tumor cell proliferation, and induction of tumor cell death [318,319,320]. Takahashi et al. demonstrated that isoprenols — farnesol (28 μM), geranylgeraniol (60 μM), and geraniol (135 μM) — aid in clearing the cellular lipid through the activation of PPARγ in HepG2 cells [321]. Another major bioactive dietary component in cruciferous vegetables, indole-3-carbinol, a potent anti-carcinogenic and anti-tumorigenic agent, was shown to degrade ERα in breast cancer cells [322, 323]. In another study, it was shown to downregulate AR expression leading to reduced PSA and proliferation in LNCaP cells [324]. Another compound, 3,3′-diindolylmethane derived from the cruciferous vegetable, was also shown to elicit NURR1 and thereby prevented UVB-induced DNA damage and cell proliferation in skin cancer cells [325, 326]. Another compound, sulforaphane, majorly found in cruciferous vegetables, has been proven to evoke anti-cancer activity partially through a Nrf2–dependent pathway, which was triggered by changes in estrogen metabolism in breast epithelial cells [327]. Furthermore, Palliyaguru et al. demonstrated that sulforaphane prevents estrogen-induced mammary tumor formation, and DNA damage by eliciting ERβ, while inhibiting the ERα at the same time in rats [328]. Furthermore, several studies have shown that sulforaphane, a dietary component, downregulates HDAC and CYP27B1via activating VDR in breast and colorectal cancer cell lines [329, 330]. It has also been shown to downregulate CYP3A4 through the inhibition of PXR in colorectal cancer cells [331].

Additionally, liquiritigenin, a plant-derived flavone with strong estrogenic activity, was demonstrated to inhibit tumor vascularization and growth by down-regulating VEGF in cervical cancer cells and xenografts [332]. Liquiritigenin in a low concentration (36 nM) acted as ERβ agonist and inhibited MCF-7 cell growth [333]. Likewise, recently, a study by Tian and their team explained that magnolol (5,5′-diallyl-2,2′-dihydroxybiphenyl), a polyphenolic compound purified from the Magnolia officinalis, plays a key role in suppressing steatosis, dyslipidemia, through the activation of PPARγ [334,335,336]. Furthermore, oridonin, a diterpenoid derived from the medicinal plant Rabdosia rubescens, was demonstrated to inhibit NF-κB signaling by activating PPARγ in MG-63 and HOS osteosarcoma cells [337]. In another study, Goto and coworkers showed that phytol, a side chain of chlorophylls, at 50 μM concentration activates both PPARα, PPARγ, and PPARδ and their target genes CPT1A, acyl-coA synthase (ACS), acyl-coA oxidase (ACO) expression in HepG2 carcinoma cells [338, 339].

Recently, Yang et al. explored that piceatannol, a stilbenoid, remarkably suppressed the intracellular fatty acid and lipid accumulation by reducing SREBP1 and CD36 in HepG2 cells. Furthermore, this study showed that piceatannol induced β-oxidation of fatty acids is FXR and PPARα dependent [340]. Another study demonstrated that PsL5F (ent-11alpha-hydroxy-15-oxo-kaur-16-en-19-oic-acid) derived from Pteris semipinnata showed an agonistic effect on Rev-Erbα in ovarian cancer cells in vitro [341]. Furthermore, 6-shogoal, a major pungent bioactive constituent of rhizomes of Zingiber officinale (ginger), was shown to arrest the cell cycle and induce apoptosis in breast and colon cancer cell lines through the activation of PPARγ at 10 μM concentration [342]. This study also illustrated that the percentage of cells undergoing apoptosis was reduced to 50% upon 6-shogaol treatment (10 μM) in PPARγ depleted MCF-7 and HT-29 in vitro which shows that PPARγ is one of the most important mechanisms of 6-shagaol induced apoptosis [342]. Another biologically active compound from the seeds of Nigella sativa, thymoquinone, has shown anti-tumorigenic effects against colorectal cancer, fibrosarcoma, leukemia, osteosarcoma, squamous cell carcinoma, and prostate cancer in various in vitro and in vivo experimental models [343,344,345,346]. Woo et al. demonstrated that thymoquinone (40 μM) mediates anti-proliferative and apoptotic effects via the activation of PPARγ and PPARβ/δ in MCF-7, MDA-MB-231, and BT-474 breast cancer cell lines [347]. In another study, Huang et al. illustrated that inclusion of a 5-μM concentration of triptolide, a bioactive component extracted from the root bark of Tripterygium wilfordii, suppressed the growth of prostate cancer cells LNCaP and PC3 and xenografts by inhibiting c-Jun and AR activities [348]. In addition, the treatment of breast cancer cells with 40 nM triptolide enhanced wild-type p53 expression, reduced cell viability, and cell cycle arrest by downregulating ERα expression [349]. Furthermore, bioactive terpenoids and isoflavones such as ginkgolide A and B, EGB 761, quercetin, and kaempferol have been shown to induce MDR1, CYP2B6, CYP3A4, UDP glucuronosyltransferase family 1 member A1 (UGT1A1), multidrug-resistant protein 2 (MRP2), and aryl hydrocarbon receptor (AhR) through activation of PXR and CAR in liver cancer cells [350]. Another isoflavone tangeretin, derived from citrus fruits, reduced CA-15–3 and breast tumor growth in vivo by the inhibition of ERα and PR [351]. In another study, cyanidin, a flavonoid abundantly found in fruits and vegetables, was shown to inhibit the lipid accumulation in hepatocarcinoma cells via the activation of LXRα and LXRβ [352]. Furthermore, diterpenes including 6,12-dihydroxyabieta-5,8,11,13-tetraen-7-one, sugiol, ferruginol, and 5-epixanthoperol derived from Cryptomeria japonica reduced prostate cancer cell growth through the inhibition of AR [353]. In another study, lignans, enterolactone, and organochlorine have been shown to induce PXR in liver cancer cells [354]. In another study, fucosterol derived from marine algae has been demonstrated to be effective against colon cancer cells through the activation of both LXRα and LXRβ [355]. Another phytochemical ethyl 2,4,6-trihydroxybenzoate purified from Celtis biondii reduced the cellular lipid accumulation in HepG2 cells through the upregulation of LXRα and LXRβ [356]. Also, iristectorigenin B, a product from Belamcanda chinensis, displayed significant agonistic activity for LXRα and LXRβ and induced the expression of ABCA1 and ABCG1 leading to cholesterol efflux in macrophages without lipid accumulation in HepG2 cells [357]. Another compound, paeoniflorin from Paeonia lactiflora, was shown to activate LXR and its targets ABCA1 and GAL4 in HepG2 cells [358]. These studies demonstrate the remarkable potential of phytochemicals in modulating the expression of NRs and exerting anti-cancer properties.

6 Effect of whole plant extracts or juice or emulsions on NR in cancer

A plethora of studies has reported that whole plant extracts and juices can be used to treat cancer and are proposed to be having better therapeutic potential compared to isolated compounds [359]. A decade of research has demonstrated that whole plant extracts also exert their anti-cancer effects through modulating NRs. For example, Wentworth et al. treated choriocarcinoma cells with St John’s wort extract and hyperforin from Hypericum perforatum and found that the extract activates PXR in these cells [360]. In another study, a whole plant extract from Zanthoxyli fructus was shown to inhibit AR activation in prostate cancer cells leading to decreased PSA, cyclin D1, Akt, and increased apoptosis [361]. Similarly, extracts of Serenoa repens have also been found to arrest the cell cycle and induce apoptosis by inactivating the AR signaling pathway [362]. In line with these studies, an aqueous extract from Psidium guajava L. remarkably inhibited PSA, cell proliferation, cell cycle, phospho-Akt, and ERK in prostate cancer cells by inhibiting AR expression [363]. In addition, dichloromethane extract of Pygeum africanum, ethanolic extract of Scutellaria baicalensis, and pomegranate juice and its extract have also been found to inhibit AR thereby reducing the proliferation of LNCaP prostate cancer cells [199, 240, 302]. Furthermore, an emulsion of pomegranate was found to inhibit ERα and ERβ in breast cancer in vivo leading to reduced β-catenin and cyclin D1 [364]. In another study, He et al. showed that the methanolic extract of Cornus alternifolia was a potent agonist of PPARα, PPARγ, and LXR in HepG2 cells [365]. In addition, two independent studies have demonstrated that dietary inclusion of blue berries and flaxseeds delayed tumor latency and induceed chemoprevention in breast cancer cells in vivo through the inhibition of ERα [366, 367]. Taken together, these studies suggest that plant-derived compounds and extracts that exert effects through one or more NRs could be potential anti-cancer drugs.

7 Zootherapeutics that modulate NRs

Zootherapy is a branch of ethnozoology concerned with the treatment of human illnesses using animal and animal-derived compounds. Since ancient times, a wide range of animals and products derived from various parts and organs of their bodies have been a reservoir of therapeutic substances used in diverse cultures. Bones, feathers, hooves, skins, toxins, tusks, venom, and other by-products of wild and domestic animals are crucial components in the formulation of curative and preventive medicines [499,500,501]. Zootherapy is an essential alternative among several other established therapies practiced in modern society. Several investigations on the anti-tumoral activities of animal-derived by-products have been conducted to combat lethal diseases such as cancer [502]. A study conducted by Jang et al. reported that the four peptides — DFHING, FHG, GFHI, and GLSDGEWQ — derived from beef hydrolysate possess strong anti-cancer activities against breast cancer (MCF-7) and stomach adenocarcinoma (AGS) cell lines [503]. ACBP-3, a bioactive peptide derived from the spleen and liver of goats, exhibited gastric and colon cancer both in vitro and in vivo [504, 505]. Moreover, numerous studies have reported the anti-cancer activities of compounds derived from cows, birds, reptiles, mollusks, and crustaceans [506,507,508,509,510,511,512,513]. In this section, we focus on the active components derived from various animal sources that exhibit agonistic and antagonistic activity against NRs and their implication in cancer prevention and treatment. Figure 6 shows the various zootherapeutic and their target NRs leading to reduced cancer hallmarks.

Fig. 6

Summary of natural compounds derived from various origins that target NRs in cancers. Zootherapeutic and microbially derived compounds markedly inhibited various hallmarks of cancer cells through the regulation of NRs. Various compounds derived from animals such as bees, corals, scorpions, sponges, and tunicates were shown to be potential agonists or antagonists of different NRs. In addition, animal metabolite–derived compounds and microbially derived compounds including gut microbes were also shown to inhibit cancer cell growth and progression through the regulation of NRs. The figure was created in BioRender.com

Natural compounds derived from marine organisms have been valued for over half a century, but growing interest in this promising novel natural medication has only recently emerged. Numerous unique compounds that modulate NRs have been discovered by chemical, structural, and pharmacological characterizations of marine natural resources [514]. Marine sponges and tunicates have been proven to be an outstanding source of novel chemical entities with anti-infectious, anti-inflammatory anti-oxidant, and anti-cancer activities [514, 515]. Mora et al. demonstrated that marine sponge Pseudoceratina rhax metabolite psammaplin A of 10 μM concentration induces apoptosis in MCF-7 breast cancer cell lines by activating PPARγ within 10 h of treatment [418]. A bioactive compound sintokamide A extracted from Dysidea species of marine sponge showed potent AR inhibitory activity when treated for one hour at a concentration of 5 μg/mL in LNCaP prostate cancer cell lines [419]. Two novel compounds, solomonsterol A and B isolated from Theonella swinhoei, were demonstrated to inhibit IL-1β expression in RAW264.7 macrophage cells in vitro. This study also showed that these solomonsterols transactivated PXR and its target genes CYP3A4 and MDR1 in HepG2 cells [420]. Moreover, in vitro studies using HepG2 cell lines showed that cholestan disulfate (10 μM), a modified solomonsterol A, isolated from Theonella swinhoei, was a potent PXR agonist [422]. Another study isolated theonellasterols B-H and conicasterols B from Theonella swinhoei methanolic extract and examined the potential role in modulating nuclear receptors [423]. This study illustrated that theonellasterols B-F and theonellasterol H antagonize the effects of FXR and act as PXR agonists when treated with hepatocarcinoma cell line (HepG2 cells) at 10 μM concentration for 18 h post-transfection stimulation in luciferase assay [423]. Theonellasterol G, however, antagonized the effects of chenodeoxycholic acid on FXR and transactivated FXR in the absence of this natural ligand indicating that theonellasterol-G is a modulator of FXR [423]. Another compound, 10 and 50 μM of conicasterol B acted as an antagonist of FXR and agonist of PXR in HepG2 cells [423]. In addition, Renga et al. revealed that theonellasterol of 50 μM concentration antagonized the effect of both natural and synthetic FXR agonists and induced the expression of SHP in HepG2 cells [424]. Another study showed that theonellasterol and its esters (10 μM) antagonized the agonist effect of chenodeoxycholic acid on FXR in HepG2 cells [425]. Another compound, conicasterol E isolated from the Theonella swinhoei showed PXR agonistic activity when treated with HepG2 cells at 10 μM concentration [426]. Similarly, another polyhydroxylated sterol, conicasterol F, derived from Theonella swinhoei showed potential PXR agonistic activity and FXR antagonistic activity in HepG2 cells at 10 μM concentration [427]. In another study, treatment of 10 μM malaitasterol A derived from Theonella swinhoei was shown to induce the transactivation of PXR in HepG2 cells [428]. In addition, 4-methylenesterols including conicasterol, conicasterol H, conicasterol J, and swinhosterol isolated from methanolic extract of Theonella swinhoei showed inhibitory activity against CDCA induced transactivation of FXR and effectively induced PXR expression in HepG2 cells when treated at 50 μM concentration[428]. Furthermore, Sepe et al. isolated conicasterol (compound 1), theonellasterol (compound 2), and preconicasterol (compound 3) from Theonella swinhoei and Theonella conica and further chemically modified preconicasterol to obtain around 25 derivatives. This study showed that compound 3 (preconicasterol) and its derivative compound 8 remarkably transactivated PXR in HepG2 cells at both 10 and 50 μM concentrations with EC₅₀ of 21 and 18 μM, respectively [445].

Festa et al. isolated thirteen new plakilactones from the marine sponge Plakinastrella mamillaris and showed that among these compounds, gracilioether B, gracilioether C, and plakilactone C act as potent non-covalent PPARγ agonists in HepG2 cells with EC₅₀ of 5, 10, and 2 μM, respectively [431]. Moreover, gracilioethers E, I, J, and K isolated from an apolar extract of Plakinastrella mamillaris sponge showed potent PXR agonistic activity when treated with HepG2 cells with 10 μM concentration [432]. Chianese et al. demonstrated that incisterols A5 (10 μM) and A6 (10 μM) derived from Plakortis cfr. lita were potent trans activators of PXR and induced the target genes CYP3A4 and MDR1 expression in HepG2 liver cancer cells [433]. In another study, Meimetis et al. showed that the methanolic extract of whole sponge Niphates digitalis and its active component niphatenone B inhibited the proliferation of LNCaP prostate cancer cells through the suppression of AR gene expression. This study also showed that niphatenone B covalently binds to the AF-1 region of NTD of AR [434]. Additionally, a sesterterpene, luffariellolide, isolated from the hexane extract of marine sponges Luffariella sp. and Fascaplysinopsis sp. was shown to inhibit the growth of breast cancer cells (MCF-7), colon cancer cells (HCT-15, HCT-116), and leukemia cells (HL-60, THP-1) at 5 μM concentration through the induction of RARα and RARβ expressions [435]. Another marine sponge-derived compound suvanine (EC₅₀ = 24 μM) and 13α-hydroxyl derivative of suvanine (EC₅₀ = 25 μM) were shown to possess excellent antagonistic activity against FXR in HepG2 cells [436]. Another novel compound, 12-deacetyl-12-epi-scalaradial, a sesterterpene isolated from Hippospongia sp., was shown to inhibit the cell proliferation of MCF-7 breast cancer cells (IC₅₀ = 36 μM), HeLa cervical cancer cells (IC₅₀ = 13.74 μM), HCT-116 colon cancer cells (IC₅₀ = 27.1 μM), and HepG2 liver cancer cells (IC₅₀ = 23.4 μM) [437]. Mechanistic studies revealed that 12-deacetyl-12-epi-scalaradial significantly inhibits phosphorylation of ERK and induces the PARP cleavage and phosphorylation of NUR77 by interacting with its LBD leading to apoptosis in HeLa cells [437].

Recently, Wu et al. demonstrated that phakefustatins A-C (kynurenine-bearing cycloheptapeptides) isolated from marine sponge Phakellia fusca suppressed the cell proliferation and induced G2/M cell cycle arrest and apoptosis in HeLa cells by inhibiting p85α (catalytic subunit of PI3K), Akt phosphorylation, and cyclin B1 and inducing PARP cleavage in RXRα-dependent manner [438]. Another novel estrogenic steroid, cinanthrenol A, isolated from Cinachyrella sp. was shown to effectively inhibit ERα and cell proliferation (IC₅₀ = 10 nM) in the cervical (HeLa) and breast cancer (MCF-7) cells [439]. This study also showed that cinanthrenol modulated the expression of ER-responsive genes including A-MYB and SMAD3 in MCF-7 cells [439]. Recently, Parrish et al. demonstrated that a novel compound, myrmenaphthol A, isolated from a Hawaiian sponge of genus Myrmekioderma inhibits ERα in the cervical (HeLa) and lymphoma (P388) cells [440].

Apart from sponges, tunicates are the potential source of numerous marine natural products. Tunicate-derived compounds such as ET-743 (FDA approved), aplidine, PM01183, and vitilevuamide have shown significant anti-cancer properties under various clinical and preclinical trials [514, 515]. Several studies have shown that tunicate-derived compounds modulate nuclear receptors at the molecular level in cancer cells. For instance, Imperatore et al. showed that phallusiasterols A (10 μM) and B (10 μM) isolated from the tunicate, Phallusia fumigata, transactivate PXR and induce the downstream target genes CYP3A4 and MDR1 in hepatocellular carcinoma cell lines [441]. The same group later demonstrated that another novel compound phallusiasterol C from Phallusia fumigata also transactivated PXR and induced the expression of CYP3A4 and MDR1 when treated with 50 μM in the same cells [442]. In another study, 15 marine natural compounds isolated from a tunicate, Ciona intestinalis, including bensulfuron-methyl, butafenacil, β-cyfluthrin, α-cypermethrin, diethylhexylphthalate, esfenvalerate, fenpyroximate, mancozeb, mesosulfuron-methyl, permethrin, foramsulfuron, gymnodimine, okadaic acid, pectenotoxin-2, and yessotoxin, were explored for their effect on xenobiotic receptors. It was observed that okadaic acid showed the highest PXR activation capacity with an EC₅₀ of 7.2 ± 1.1 nM in HepG2 cancer cells. The other compounds which activated PXR in these cells include bensulfuron-methyl (EC₅₀ = 89.4 ± 5.5 μM), butafenacil (EC₅₀ = 6.0 ± 0.5 μM), β-cyfluthrin (EC₅₀ = 2.5 ± 0.3 μM), α-cypermethrin (EC₅₀ = 1.6 ± 0.2 μM), diethylhexylphthalate (EC₅₀ = 1.8 ± 0.2 μM), esfenvalerate (EC₅₀ = 1.5 ± 0.2 μM), and permethrin (EC₅₀ = 5.6 ± 0.6 μM) [443].

Increasing lines of evidence showed that bee-derived compounds including honey and venom possess potential anti-cancer activities such as cell cycle arrest, apoptotic induction, mitochondrial permeabilization, anti-inflammatory effect, and immunomodulation [516, 517]. Mechanistic studies have shown that the anti-cancer activities of these substances are attributed to NR modulation. For instance, nemorosone derived from Cuban propolis of bee inhibits the proliferation of MCF-7 breast cancer cells through the downregulation of ERα [447]. Khamis et al. demonstrated that treatment of MCF-7 cells with bee venom, piperine, and hesperidin combination effectively inhibits ERα [278]. Another study by Moutsasou et al. showed that 10-hydroxy-2-decenoic-3,10-dihydroxydecanoic-3 sebacic acid derived from royal jelly exerts anti-cancer effects by activating ERβ in MCF-7 cells [448].

Moreover, a plethora of studies has shown that scorpion venom, a complex mixture of biogenic amines, mucoproteins, nucleotides, neurotoxins, organic salts, peptides, and proteins, possesses immense anti-cancer potential due to its cytotoxic, immunosuppressive, anti-proliferative, and pro-apoptotic properties [518, 519]. Zhao et al. demonstrated that scorpion venom–derived peptide, mucroporin-M1, inhibited hepatitis B virus (HBV) capsid DNA, intracellular HBV RNA replication intermediates, and HBV core protein in the cytoplasm and reduced the amount of extracellular HBsAg, HBeAg, and HBV DNA productions in HepG2.2.15 hepatocellular carcinoma cells. This study also showed that the mucroporin-M1 inhibited HBV replication through MAPK pathway–mediated down-regulation of HNF4α [449].

These studies suggested that animal-derived products possess anti-cancer effects by markedly modulating numerous nuclear receptors including AR, ER, FXR, HNF4α, and PXR. However, further preclinical and clinical studies need to be conducted to validate their potentiality as anti-cancer drugs.

8 Metabolite-derived compounds targeting nuclear receptors in cancer

Increasing lines of research have proved that numerous metabolites regularly generated as byproducts of cellular metabolisms, such as those containing reactive groups or those that operate as competitive analogs against other metabolites, are highly cytotoxic [520]. Hence, by tackling the downstream enzymes in a metabolic pathway that produces a toxic byproduct or by treating the cancer cells with these compounds, we might be able to provoke the accumulation of this cytotoxic metabolite and destroy cancer cells [520]. Attia et al. demonstrated that obeticholic acid, derived from chenodeoxycholic acid, inhibits the cell cycle, invasion, and migration of HepG2, Huh7, and SNU-449 hepatocarcinoma cells by activating FXR resulting in reduced IL-6, phospho-STAT3, IL-1β, and upregulation of SOCS3 expression [470]. In another study, 5-oxo-6,8,11,14-(E,Z,Z,Z)-eicosatetraenoate, a derivative of arachidonic acid, was shown to hamper the breast cancer cell proliferation through the activation of PPARγ [521]. Administration of tocopherol (vitamin E) in cancer-bearing mice has been shown to retard tumor growth and induce cancer cell apoptosis through the activation of either PPARγ, or ERβ, and inhibition of ERα [466,467,468]. In addition, γ-tocopherol and vitamin E administration through diet has been illustrated to upregulate PPARγ and reduce cell proliferation of SW-480 colon cancer cells [455]. Moreover, the addition of all-trans retinoic acid and 9-cis-retinoic acid in the culture medium of T3M-4, AsPc-1, and BxPc-3 pancreatic cancer cells promoted cell death via the activation of RARγ [454]. Two independent studies conducted on lymphoma and leukemia cell lines explored the anti-cancer properties of prostaglandin 15d-PGJ2. It was observed that 10 μM 15d-PGJ2 downregulates STAT, NF-κB, Ap-1, cyclin-dependent kinase inhibitor 1A, adipophilin, microphage activation, and inducible nitric oxide synthase (iNOS) in these cells by activating PPARγ [451, 452]. In addition, treatment of prostate cancer cells with 15S-hydroxyeicosatetraenoic acid arrested cell cycle through the activation of PPARγ [453]. Studies have also shown that LDL rich in 3-polyunsaturated fatty acids (3-PUFA) isolated from African green monkeys and vervet monkeys upregulates PPARγ and syndecan-1 leading to apoptosis of breast cancer cells [460,461,462]. Similarly, compound 4k derived from PUFA-alkanolamine reduced inflammatory cytokine production such as IL-6, NF-κB, IL-1β, and TNFα in lung cancer cells in NUR77-dependent manner [471]. Another study showed that treatment of Burkitt B-cell lymphoma cells with docosahexaenoic acid–induced caspases and cell death in a dose-dependent manner activated PPARγ in these cells [465]. Interestingly, a study showed that the addition of aglycones and their metabolites isolated from the urine of human subjects on a tofu diet to growth media reduced breast cancer cell proliferation via activating PPARγ [456]. Another bioactive metabolite sodium gluconate inhibited carcinogen-induced tumor growth in the colon of male Fischer-344 rats by activating RXRγ and RARα [464]. Furthermore, α-linolenic acid, linoleic acid, and their conjugates have been shown to retard tumor cell proliferation and activate apoptotic pathways in various cancer models such as bladder cancer, breast cancer, colon cancer, gastrointestinal cancer, glioblastoma, and hepatocarcinoma [457,458,459, 463, 469]. Although metabolites have shown beneficial effects in preventing cancer growth, obtaining a wide library of pure and sufficient quantity of metabolites is a key problem.

9 Microbial products targeting nuclear receptors in cancer

Recently, microbially derived compounds have gained tremendous momentum in drug development and research [522]. Growing lines of experimental evidence indictate that microbially derived compounds contain high pharmacological and medicinal properties. Figure 6 shows the various microbial extracts and their derived compounds that target NRs leading to reduced cancer hallmarks.Tabata et al. explored the non-steroidal and selective PR modulator nature of PF1092A, PF1092B, and PF1092C extracts isolated from the rare fungus P. oblatum PF1092. PF1092A demonstrated an excellent and moderate affinity for porcine and human PR respectively, in in vitro receptor binding assays and it partially activated PR in T47D human breast cancer cells. However, derivative of PF1092C showed better binding affinity in both the PR receptors with lower cross-reactivity nature for other steroidal receptors [472].

In a study, Xie and coworkers explored the efficacy of isolated compounds from the liquid culture of Penicillium granulatum MCCC 3A00475, a deep sea–derived fungus. It was observed that out of five penicisteroids D − H isolated, two showed potent RXRα binding affinity. These compounds (50 μM) also exhibited anti-proliferative attributes in A549 lung cancer cells by arresting the cell cycle in the G0/G1 phase and upregulating PARP cleavage leading to apoptosis via RXR-dependent mechanisms [483]. In another study, a combinatorial approach of polysaccharides extracted from Ganoderma lucidum (Lingzhi) (750 mg/kg BW), along with the saponins isolated from Gynostemma pentaphyllum (300 mg/kg BW), showed a reduction in polyps, the shift of colonic M1 to M2 macrophages, and ameliorated inflammatory gut barrier in ApcMin^/+ colon cancer murine models. The treatment resulted in decreased levels of phospho-STAT3, iNOS, and Src oncogene with modulation of G-protein coupled receptor (GPCR) signaling. In addition, this study demonstrated that GPCR induced the signaling effects in association with PPARγ [484].

In another study, Zhan et al. isolated octaketide cytosporone B (Csn-B) from Dothiorella sp. HTF3, an endophytic fungus that served as an agonist for the orphan receptor Nur77. In this study, the authors demonstrated the strong binding affinity of Csn-B towards the Nur77, with its strong apoptotic action through translocalization of Nur77 from the nucleus to the mitochondria. Moreover, Csn-B treatment (5 μg/ml) suppressed 70% growth of BGC-823 human gastric cancer cells and SW620 human colon cancer cells with tumor retardation in the xenograft models [477]. In another study, β-glucan isolated from Lentinus edodes (LNT) was explored for its anti-proliferative effects by downregulating Nur77/HIF-1α axis in breast cancer. This study showed that LNT (20 mg/kg BW for 2 weeks) abrogated the development of breast tumors in MMTV-PyMT transgenic mice, and their potential to metastasize to the lungs was associated with a decrease in HIF-1α levels in tumor tissues. Further, LNT was shown to inhibit hypoxia-induced HIF-1α in a Nur77 concentration-dependent manner in vitro, which may be mediated through the ubiquitin–proteasome pathway [486].

Sondergaard and his colleagues explored the anti-tumorigenic and agonist activity of fusarin C extracted from Fusarium graminearum and F. avenaceum. Treatment with fusarin C promoted the proliferation of the MCF-7 breast cancer cell lines in a concentration-dependent manner (up to 50 µM) implicating that it acts as an estrogenic agonist and should be categorized as a mycoestrogen. In this study, fusarin C’s toxicity was found to be equivalent to that of other mycoestrogens such as zearalenone. However, its molecular structure was substantially distinct from other known estrogen agonists. In addition, fusarin C toxicity was also investigated in five other human cell lines, Caco-2, U266, PC3, MDA-MB-231, and MCF-10A, where it showed anti-proliferative effects in all the cell lines [488].

Equol is a metabolite derived in vivo by gut bacteria from the metabolism of soy phytoestrogen daidzein. As equol is known to be estrogenic, human exposure to it might have significant biological consequences. Equol is known to possess a chiral molecule with two enantiomers: R-equol and S-equol. Muthyala et al., in 2004, studied the binding and transcriptional activity of the equol enantiomers with ERα and ERβ. It was found that the R isomer exhibited ERα binding selectivity, whereas S isomer had limited ERα selectivity in in vitro transfection tests using HEC-1 human endometrial carcinoma cells [473]. Similar results were found in another study, where the effects of equol R- and S-enantiomers were investigated on the motility and invasion of PC3 and DU145 human prostate cancer cells. It was observed that R-equol and S-equol suppressed motility and invasion by downregulating MMP-2 and MMP-9 levels in PC3 and DU145 cells in a dose-dependent manner [474].

Bassiatin, a natural compound isolated from Fusarium oxysporum J8-1–2. It was observed that treatment with bassiatin (24 μM) suppressed estrogen-dependent cell proliferation in MCF-7 ERα breast cancer cells. Furthermore, bassiatin (24 μM) in combination with 17β-oestradiol (10 nM) inhibited the mRNA and protein levels of ERα and the estrogen-responsive gene cyclin D1 with enhanced phospho-cyclin D1(Thr286) levels [489]. In a study, indolepropionic acid (IPA), a gut microbiome tryptophan metabolite, was explored for its anti-neoplastic activities in breast cancer. It was observed that IPA is cytostatic and selectively abrogates the growth of SKBR-3 and 4T1 breast cancer cells while having no impact on non-transformed primary fibroblasts. Moreover, IPA treatment mediated the downregulation of NRF2, upregulation of iNOS, and increased mitochondrial reactive species production. It was found that IPA exerted its anti-tumorigenic effects through the activation of the pregnane X receptor (PXR) receptor and aryl hydrocarbon receptor (AHR) [495]. Zhao and his coworkers isolated a novel indole diterpenoid compound, drechmerin H, from the fermentation broth of endophytic fungal Drechmeria sp. SYPF 8335 was found in the roots of Panax notoginseng and evaluated its activity against the human PXR. It was shown that drechmerin H had a significant agonistic activity for the PXR by in silico docking studies, which was validated by in vitro in HepG2 cell lines (EC₅₀ of 134.91 ± 2.01 nM) [493].

In one of the studies, it was observed that the anti-tumor effects of the bacterial metabolite lithocholic acid (LCA) were dependent on oxidative stress caused by the LCA treatment (0.3 µM), leading to downregulation of the NRF2/kelch-like ECH-associating protein 1 (Keap1) pathway and the activation of iNOS and therefore nitrosative stress in MCF7, SKBR-3, and 4T1 breast cancer cell lines. In addition, LCA-mediated anti-neoplastic effects were through the activation of CAR and Takeda G-protein coupled receptor (TGR5) [494]. Nepelska and his coworkers explored commensal gut bacteria’s efficacy in modulating the transcriptional expression of PPARγ. The presence of butyrate and propionate, two of the primary metabolites of gut bacteria, was associated with the activation of PPARγ activity via ERK1/2 signaling. Notably, two strains a Prevotella and an Atopobium were chosen for further investigation, and it was found that they upregulated two PPAR-target genes, angiopoietin-like 4 (ANGPTL4) and adipose differentiation–related protein (ADRP) [491].

Taken together, there is an immense potential for the microbially derived compounds to serve as agonists/antagonists in modulating the transcriptional potential of the NRs, which could pave the way for the development of novel targets for cancer prevention and treatment.

10 Clinical trials

Several studies have reported the anti-cancer properties of natural compounds through the modulation of NRs. However, only a few of these natural compounds are shown to target NRss at clinically significant levels. In this section, we summarize the clinical trials conducted on natural compounds and their reported NRs targeting activities. The clinical trials of various natural compounds that showed to target NRs in humans are listed in Table 3.

Table 3 The clinical trials that show the potential of natural compounds that target NRs and their anti-cancer effects

In a phase II clinical study, Zhang et al. demonstrated that the administration of lycopene, a carotenoid, of 10 mg/day for 174 days effectively reduced the circulating PSA levels in prostate cancer patients (n = 41). The mechanistic studies using prostate cancer cells in vitro showed that lycopene remarkably reduced AR expression leading to retarded growth and progression of these cells [527]. In another randomized controlled trial, supplementation of soy protein isolates (40 g/day) for 6 months was shown to significantly suppress the AR expression in the prostate post-intervention biopsy samples compared to pre-intervention biopsy samples [526].

A plethora of studies has shown that irinotecan, a semisynthetic analog of the natural compound camptothecin, possesses tremendous anti-cancer activities [530,531,532,533]. Numerous clinical trials have demonstrated that irinotecan modulates NRs in cancer patients. For instance, in phase I clinical trial, coadministration of FLOFIRI (2400 mg/m² of 5-fluorouracil, 200 mg/m² of levo-leucovorin, and 180 mg/m² of irinotecan) along with efatutazone (0.25 mg and 0.5 mg) was shown to safely and effectively increase the stable disease period in metastatic colorectal cancer patients (n = 15) [525]. This treatment regimen was shown to reduce PPARγ and RXR after intervention in tumor specimens of patients with stable disease compared to patients with progressive disease, although the difference was not statistically significant [525]. Another well-recognized chemotherapeutic agent, doxorubicin (a natural anthracycline antibiotic), was shown to reduce ABCA1 via downregulating PPARγ and LXRα in breast cancer patients (n = 12) [523]. In another double-blind randomized clinical trial, consumption of Berberis vulgaris juice (480 mL/day) for over 8 weeks was shown to downregulate PPARγ, HIF, and VEGF in women with benign breast diseases [524]. This study also showed that consumption of B. vulgaris juice for 8 weeks did not show any adverse side effects in these patients [524]. In a double-blind, placebo-controlled, and randomized clinical trial supplementation of curcumin (100 mg) along with soy isoflavones (40 mg) for 6 months was shown to significantly reduce PSA levels in the patients with either prostate cancer or prostate intraepithelial neoplasia (n = 85). The same study showed that curcumin and isoflavone combinatorial treatment reduce AR expression in LNCaP prostate cancer cells suggesting that the AR is a potential molecular target of these drugs [528]. In addition, the safety evaluation showed that curcumin and isoflavone combinatorial treatment did not cause any adverse side effects in prostate cancer patients [528].

Furthermore, monoclonal antibodies have been proven to be potential anti-immunotherapeutic agents and aid in disease relapse in chemoresistant cancer patients [534,535,536,537]. Certain monoclonal antibodies are direct modulators of NRs. For example, intravenous administration of figitumumab (monoclonal antibody targeting IGF 1 receptor) at 20 mg/kg every 3 weeks for three cycles decreased the PSA levels and AR expression in localized prostate cancer patients (n = 16) [538]. In another clinical study, avelumab (targets PD-L1) administration (10 mg/kg, intravenous) was shown to be effective against refractory prostate cancer treatment by altering the plasma concentration of AR [529]. The study also evidenced the acceptable toxicity for the avelumab treatment of mentioned dosage [529].

Furthermore, the pharmacodynamics and pharmacokinetics of a well-known chemotherapeutic drug, docetaxel, have been shown to be dependent on single nucleotide polymorphisms (SNPs) in CAR, HNF4α, PXR, and RXR in Chinese nasopharyngeal cancer patients and Asian breast cancer patients [539, 540]. Another study by Deeken et al. showed that the SNPs in PPARδ were significantly associated with therapeutic response to docetaxel in prostate cancer patients [541].

Collectively, these clinical trials suggest that natural compounds exert their anti-cancer effects through the modulation of NRs and are well-tolerated in cancer patients. However, further studies are required to bring them to the bedside.

11 Conclusion and future perspectives

Several NRs have the potential to be used as cancer therapeutics. As detailed in this review, many established medicines or current clinical studies are based on the activation of single or multiple NRs, either as a standalone treatment or in conjunction with existing chemotherapy or immunotherapy. However, one of the most critical challenges in the sector is the occurrence of adverse side effects, which can arise after extended therapy. This obstacle is also why the development of first-generation LXR ligands was halted before reaching the clinics. The development of resistance to NR ligands is the field’s second significant stumbling block. In recent years, traditional medicine has shown a substantial success rate, with increased efficacy and fewer side effects. In addition, many natural products are known to sensitize cancer cells to chemotherapeutic drugs. Therefore, natural products can be used as more effective agents than chemotherapeutic drugs.

Phytochemicals have been developed as potential cancer therapeutics for more than a couple of decades and have shown a wide range of targets both at gross and molecular levels. Phytochemicals of class alkaloids such as berberine, caffeine, capsaicin, and piperine; carotenoids such as astaxanthin, β-carotene, bixin, capsanthin, cryptoxanthin, fucoxanthin, and apo-10′-lycopene; and polyphenols such as acetylshikonin, artemisinin, auraptene, baicalein, N-butylidenephthalide, celastrol, cryptotanshinone, curcumin, ellagic acid, embelin, emodin, genistein, guggulsterone, gypenoside XLIX, hesperidin, honokiol, morusin, resveratrol, and withaferin A have been reported as modulators of human NRs at concentrations ranging from 25 to 200 μM. Several of these, including piperine, curcumin, genistein, guggulsterone, and resveratrol, have shown profound anti-cancer activities with minor adverse side effects in preclinical and clinical settings. Low bioavailability, solubility, and accuracy restricted these phytochemicals to develop as commercial drugs. Recently, nanoformulations of these compounds also had shown improved bioavailability and accuracy at the molecular level with lesser concentration usage in clinical trials. The drugs docetaxel, and paclitaxel, and their nanoformulations have been the most successful chemotherapeutic agents against several malignancies including bladder, brain, breast, colon, cervical, head and neck, leukemia, pancreatic, and prostate. In the randomized clinical trials, these compounds were shown to be not effective among certain patients who have SNPs in NRs. Therefore, more studies are required to determine how these compounds affect NRs.

A variety of zootherapeutic agents have shown profound anti-oxidant, anti-inflammatory, and anti-cancer activities. The in vitro studies have shown that marine animal–derived products and extracts inhibited proliferation and induced apoptosis of cancer cells through modulating NRs including FXR, PXR, LXR, and AR, and the expression of their downstream target genes. Most of these compounds including psammaplin A (10 μM); sintokamide A (5 μg/mL); solomonsterols A (5.2 μM) and B (50 μM); cholestan disulfate (10 μM); theonellasterols B–F (10 μM); theonellasterol H (10 μM); theonellasterol G (50 μM); conicasterol B (10 μM); conicasterol E (10 μM); malaitasterol A (10 μM); gracilioethers E, I, J, and K (10 μM); and cinanthrenol A (10 nM) have been shown to remarkably modulate NRs at very low concentrations and thereby limit cancer cell growth and progression. Although a significant amount of evidence about anti-cancer mechanisms is available for these novel compounds, in vivo and clinical studies are lacking. This might be owing to the fact that these species are under continuous threat due to increased pollution, and the second reason is the difficulty and laborious synthesization of these compounds commercially.

Next, the accumulation of numerous secondary metabolites has been shown to be detrimental to cancer cells. This idea was utilized successfully in the preclinical studies and treatment of cancer cells with secondary metabolites including obeticholic acid, eicosatetraenoate, tocopherols, retinoic acid, PUFA, sodium gluconate, α-linolenic acid, and linoleic acid were shown to inhibit cell proliferation, induce apoptosis, and downregulate STAT and NF-κB pathways in cancer cells through modulating NRs. However, the efficacy, safety, and toxicity of these compounds are yet to be tested in appropriate clinical settings with blindfold and placebo-controlled trials.

Moreover, decades of research have proven the beneficial effects of microbiota on human health. One of the most successful chemotherapeutic FDA-approved agents, doxorubicin, is an antibiotic isolated from Streptomyces peucetius var. caesius. In vitro and in vivo have shown that microbial products and extracts significantly modulate NRs in several cancers. Not only that these compounds were shown to target NRs of class hormonal receptors (ER and PR) and metabolic receptors (FXR and PXR) but also certain orphan receptors including CAR and NUR77. In the future, clinical studies must be conducted to prove their efficacy against human cancers.

Furthermore, the current literature rightly points out that there is an enormous amount of evidence present to prove the effectiveness of natural compounds as modulators of NRs in various in vitro and in vivo cancer models. The majority of these cancer models include breast, liver, and prostate cancers. Nevertheless, studies regarding the role of these chemicals or extracts in modulating NRs during EMT and metastasis are scarcely leaving the question open for appropriate dosage and the choice of the right drug for the specific type and stage of cancer. Another major limitation lies in the limited knowledge about all the NRs. Therefore, in-depth studies are required to unravel the structure, mechanism of action, ligand binding, etc. Endocrine NRs such as ER, PR, and AR have been known for more than a decade, and various synthetic and natural compounds are studied for their potential to modulate these NRs. Recently, NRs involved in metabolisms, such as FXR, LXR, PPARs, RAR, RXR, PXR, and VDR, and orphan receptors such as NURR1 and NUR77 have been the center of attraction for the development of various agonists and antagonists. However, studies on whether the natural compounds affect other NRs such as COUP-TFI, COUP-TFII, DAX-1, ERRα, ERRβ, GCNF, GR, MR, CAR, ERBB, LRH-1, NOR-1, PNR, Rev-Erbα, Rev-Erbβ, RORA, RORB, SHP, TLX, TR2, and TR4 are unexplored.

In conclusion, the use of natural compounds has emerged as a novel alternative in cancer therapeutics with lower side effects, lesser cost, unique structures, and mechanisms. These drugs suppress cancer cell growth, proliferation, and invasion by blocking or activating NRs resulting in the modulation of multiple signaling pathways that induce apoptosis, arrest in the cell cycle, boost autophagy, and reverse EMT changes. The present review also discusses the efficacy of phytochemicals that target NRs as anti-cancer drugs in various in vitro and in vivo models. Additionally, this review also emphasized animal and microbially derived compounds as agonists/antagonists to NRs in cancer therapy. Together, these data suggest that natural product–derived medications are attractive prospects in anti-cancer therapeutics that need additional investigations to better understand the mechanisms by which they work. As pointed rightly in the present work, an immense variety of natural compounds are evaluated in vitro and in vivo for their anti-tumor activities as either agonists or antagonists to NRs. However, only a few clinical trials for these chemicals are performed, leaving the overwhelming majority of natural compounds untested in clinical settings. In addition, care should be taken to determine the effective dose, bioavailability, and toxicity of these compounds if any.