Keywords

17.1 Introduction

Noncoding RNAs (ncRNAs) are RNAs which are transcribed from gene sequences but are not translated like coding RNAs (mRNA) (Santosh et al. 2014). In eukaryotes, 98% of transcripts are ncRNAs which are involved in the coordination and modulation of gene expression by binding with chromatin structure, DNA or RNA (Mattick 2001). These noncoding RNAs are further divided into short noncoding RNAs (sncRNAs) and long noncoding RNAs (lncRNAs) based on size. Both short and long ncRNAs are further subdivided into 3 types. In addition, there are certain newly identified ncRNAs (Fig. 17.1) and all are playing an important role in the regulation of cellular homeostasis (Taft et al. 2010; Santosh et al. 2014). The lncRNAs are made of >200 nucleotides which are actively involved in various biological processes such as epigenetic chromatin control, promoter specific gene regulation, mRNA stability, and X-chromosome inactivation (Hombach and Kretz 2016). In contrast, the length of sncRNAs varies between 18 and 200 nucleotides and is important for translation, RNA processing, and RNA decay. Further, these sncRNAs are also involved in physiological (neuronal development) and pathological processes (metabolic disorders and tumorigenesis) (Li et al. 2021a).

Fig. 17.1
A classification of R N A that leads to coding R N A, non-coding R N A, and other classes of R N A. Non-coding R N A is classified into translation-related R N A, short non-coding R N A, and long non-coding R N A.

Different classes of RNA. miRNAs micro-RNAs, piRNAs PIWI-interacting RNAs, siRNAs small interfering RNAs, xiRNAs X-inactivation RNAs, sdRNAs Sno-derived RNAs, moRNAs microRNA-offset RNAs, tdRNA tRNA-derived RNAs, MSY-RNAs MSY2-associated RNAs, tel-sRNAs telomere small RNAs, crasiRNAs centrosome-associated RNAs

Full size image

The abundantly expressed concerved lncRNAs sequences adjacent to the protein coding gene loci of brain tissues was found to be involved transcriptional regulation or in nervous system development (Ponjavic et al. 2009). These lncRNAs and circular RNAs play an important role in CNS development, plasticity, and aging in various neurological conditions (Salvatori et al. 2020). Roberts et al. reported the involvement of lncRNA in the regulation of pluripotency of stem cells and its differentiation to form neurons and glia (Roberts et al. 2014).

Among the various ncRNAs, micro-RNAs (miRNAs) play an important role in the regulation of gene expression by binding with complementary mRNA transcripts and reduce protein synthesis (Ambros 2004; Bartel 2004; Alles et al. 2019). These miRNAs belong to snc-RNAs which are 22 nucleotides long, synthesized from intergenic and intragenic genomic regions as long primary transcripts and converted into mature miRNAs (Negrini et al. 2009). Some of the miRNAs can act as oncogenes (induce tumor formation) or tumor suppressor genes (block tumor formation) depending on the tissue target in which it is dysregulated (Garzon et al. 2009).

Natural compounds derived from plants such as curcumin, resveratrol, and quercetin were found to modulate the expression of many lncRNAs involved in the cancer and chronic diseases such as Alzheimer’s diseases, diabetes, rheumatoid arthritis, ocular diseases, and cardiovascular diseases (Saghafi et al. 2019). Thus, this article focuses on the role of different ncRNAs including miRNAs in the development and progression of cancer and neurological disorders. Further, we discussed the therapeutic potential of natural compounds in the prevention and treatment of cancer and neurological disorders by reversing the activity of ncRNAs.

17.2 Advancements of Natural Compound in Neurological Disorders and Cancer by Controlling Noncoding RNAs

Noncoding RNAs (ncRNAs) transcribed from a significant portion of genome in different brain cells play an important role in the neural development, as well as in neuropathological changes (Bian and Sun 2011). In particular, the upregulation or downregulation of micro-RNAs (miRNA) is known to be involved in various neurological conditions including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis, brain tumors, as well as in various rare neurological and neuropsychiatric disorders (Vieira et al. 2018). These ncRNAs are also used as biomarkers (Simionescu et al. 2022; Cente et al. 2022).

ncRNAs plays an important role in the physiological development of nervous system through various stages of neuronal differentiation by involvement in gene expression control at the transcriptional, epigenetic, and posttranslational levels (Salvatori et al. 2020). Further, if the genes (under the control of noncoding RNA) of the following secondary proteins (RMST, EVTs, PnKy, MALAT1, NEAT1, etc.) were mutated, this can activate different secondary messengers in various neurological diseases (Salvatori et al. 2020; Ramos et al. 2015). Therefore, alteration of noncoding RNA expression may broadly lead to formation of aberrant protein molecules (Salvatori et al. 2020). For instance, PnKy is a noncoding RNA expressed high in dividing neural stem cells and declines through neuronal differentiation. PnKy is also interacts with the splicing regulator polypyrimidine tract binding protein (PTBP-1) and regulates the appearance of multiple proteins and alternative splicing of a core set of targets that found in neurogenesis (Ramos et al. 2015). Numerous examples of mutated noncoding RNA have been identified in various neurological disorders including AD, peripheral neuropathy, central neuropathy, PD, brain malignancies, traumatic brain injury, spinal muscular atrophy, etc. (Salvatori et al. 2020; Abdolmaleki et al. 2017). In spinal muscular atrophy of SMN-1 gene mutations, noncoding RNA produces dysfunctional survivor motor neuronal (SMN) protein due to mutations of the splicing process, and consequently different phenotypes of spinal muscular atrophy can occur among the patients (Salvatori et al. 2020).

17.2.1 Alzheimer’s Disease (AD)

AD is a neurodegenerative disorder described by the accumulation of amyloid beta (Aβ), the presence of transactivating DNA-binding protein-43 (TDP-43) inclusions, and the accumulation of hyperphosphorylated and ubiquitinated tau proteins (p-tau) and neurofibrillary tangles (NFTs) (Lei et al. 2021), while specific markers are not identified so far. Studies have shown that dysfunctional regulation of miRNA is responsible for the deposition of Aβ, tau protein, neuroinflammation, as well as synaptic failure, which may contribute to the development and progression of Alzheimer’s disease (Kou et al. 2020). Further, decreased expression of miRNAs such as miR-9, miR-29, miR-101, miR-107, miR-124, miR-298, and miR-328 is shown to enhance the levels of Aβ in animal models of AD. Natural compounds such as Magnolol, a compound from Magnolia officinalis, cannabidiolic acid, N-trans-caffeoyltyramine, and cannabisin B from hemp seeds have been shown to reverse AD in mice model by inducing the expression of various miRNAs including miR-200c (Chen et al. 2022; Di Palo et al. 2022). In amyloid beta accumulation, a gene called Sortilin Related Receptor (SORL-1) produces SORL-1 antisense RNA (SORL1-AS), which drives a splicing shift of SORL-1 from synthesis of the canonical long protein variant A to differently spliced protein isoform (Salvatori et al. 2020). This step leads to accumulation of beta amyloid within the neurons and results in development of Alzheimer’s disease (Salvatori et al. 2020). While these findings strongly suggest potential role of miRNAs in the pathogenesis of AD, their prospective impact on the development and progression as well as the therapeutic options for AD are warranted.

17.3 Natural Compounds in the Regulation of Noncoding RNAs in Other Neurological Conditions

Upregulation of miR-23a and miR-27a has an important role in neuronal protection through inhibiting apoptosis pathway in traumatic brain injury (Sabirzhanov et al. 2014). Upregulation or downregulation of many miRNAs was shown to play an important role in the development of PD by altering autophagy and α-synuclein mediated inflammation (Zhang et al. 2022). For example, miR-155-5p was heavily expressed in PD and triggers α-synuclein mediated inflammation (Thome et al. 2016). Natural product berberine was found to be effective in preventing PD by regulating the expression of miR-142-5p and inhibiting the NF-kB signaling pathway (Li et al. 2021b). Increased expression of miR-124, miR-335, miR-17-5p, miR-221, and miR-228 was found to be responsible for the development of various depressive disorders (Yang et al. 2020; Li et al. 2015; Shi et al. 2021). Luteolin is likely a choice of drug for the treatment of Breast Cancer Related Depression (BCRD) since it is known to inhibit hippocampal inflammation and neuronal cell pyroptosis by regulating miR-124-3p and related signaling pathways (Zhu et al. 2022). In addition, curcumin also shows antidepressant effect by regulating the miR-124 which in turn increases the transcription of brain derived neurotropic factor (BDNF) in stress induced depression (Yang et al. 2015b). Boswellic acid is plant derivative from genus Boswellia that showed improvement in inflammation associated with cognitive dysfunction in modulating the expression of miR-155 in mice model (Sayed et al. 2018).

Another important example of noncoding RNA that plays a role in one or more of the neurological conditions is the nuclear paraspeckle assembly transcript (NEAT-1 & 2) that is ubiquitously appears to have a scaffold role in creation of subnuclear bodies termed paraspeckles (Salvatori et al. 2020). The NEAT-2 is overexpressed in an early stage of pathogenesis of amyotrophic lateral sclerosis (ALS) (Salvatori et al. 2020). While in brain malignancies, there are multiple proteins dysregulation due to noncoding RNA gene mutation. For example, in glioblastoma multiform (GBM), H-19 is an oncogenic protein upregulated by those malignant neurons, which function to resist temozolomide medication (Mahinfar et al. 2022) where overexpression of miR-21 and miR-196 is known to contribute to the development of GBM (Guan et al. 2010). However, miR-378 inhibits the development of GBM along with curcumin and enhances the apoptosis (Li et al. 2017). Further, curcumin decreases the size of glioblastoma by inducing miR-146a (negative regulator of NF-kB signaling) and miRNA-378 and affects the tumor growth (Wu et al. 2015; Li et al. 2017). Another compound, apigenin, a flavonoid from fruits and vegetables, was found to regulate the expression of miR-16 and inhibits growth of glioma (Chen et al. 2016). Sulforaphane found in broccoli, cabbage, cauliflower, and kale was found to reduce tumor growth by enhancing miR-15b-5p level, apoptotic pathway (Gasparello et al. 2022). A nutraceutical derived from sweet potato, Delphinidin-3-rutin exhibits a suppressive effect on glioma cells by induction of miR-20b-5p/Atg7 mediated autophagy (Wang et al. 2022).

Additionally, small nuclear RNA host gene 12 (SNHG-12), ubiquitin-protein ligase (MDM2), micro-RNAs such as miR-7, miR-32a, etc. were shown to play various roles in the development and progression of GBM (Mahinfar et al. 2022).

17.4 Natural Compounds and Noncoding RNAs Role in Diabetic Mediated Neurological Disorders and Cancer

The neurodegenerative disorders in diabetes mellitus are vary. One of the most important ailments is the cognitive impairment. A study investigated the effect of resveratrol, a polyphenol from grapes exerts antioxidant effect (El-Sayed et al. 2022). The resveratrol enhances the expression of miRNA-21, which in turn increases neurogenesis and angiogenesis. This can increase the formation of new blood vessels to supply more blood to the neurons (El-Sayed et al. 2022). Diabetes mellitus also increases the levels of miR-146 and miR-9, which have shown an impairment of cognitive function in mice model through activation of different pathways such as NF-kB, TNF, apoptotic pathways. Quercetin a flavonoid derived from green tea, berries, and onion can downregulate miR-146a and miR-9 and enhance learning and memory improvement in diabetic mice (Ebrahimpour et al. 2020). Oleanolic acid is a plant product that upregulates the level of miRNA-142-5p and downregulates PTEN level in diabetic animal model to eventually attenuate the inflammation associated with the mesangial cell injury (Chen et al. 2019) (Table 17.1).

Table 17.1 Natural compounds and noncoding RNAs in diabetic mediated neurological disorders and cancer
Full size table

17.5 Phytochemicals and Natural Compounds in Cancer Treatment

In the clinical scenario, cancer is mainly treated by chemotherapeutic compounds along with other oncotherapeutic methods. Some of the compounds are naturally isolated and some are synthetic compounds. Terrestrial plants have broadly discovered sources of anticancer compounds, and they are called phytochemicals. The chemical structure-based classification of phytochemicals is (flavonoids) phenolics by 45%, terpenoids and steroids by 27%, alkaloids by 18%, and other chemicals by 10% (Koche et al. 2016).

Besides phytochemicals, other floras and faunas like bacteria, fungi, algae, lichens, and marine invertebrates and their extracts have anticancer properties. Doxorubicin is one of the bacterial extracts used for solid tumors of the ovary, uterus, breast cancer, osteosarcoma, esophagus, and hematological cancer. Pheophytin, phycocyanin, and fucoidans are algal products that have anticancer activity in lung cancer, skin cancer, and other cancer forms (Sharif et al. 2014). The fungal extracts polysaccharide-rich extracts from Trametes Versicolor and Grifola Frondosa are having an antiproliferative and anti-invasive effect in colon cancer cells (LoVo and HT-29 human colon cancer cells) (Daniel Roca-Lema et al. 2019). The lichen extract Physciosporin is a secondary metabolite, isolated from Pseudocyphellaria coriacea abridged metastasis of lung cancer cells by reducing the expression of the N-cadherin and KITENIN (KAI1 C-terminal interacting tetraspanin)-mediated AP-1 activity, the lichen extract benzoic acid, 2,4 dihydroxy, 6 methyl-methyl esters from Rocella montagnei, and other compounds from Parmotrema reticulatum, Parmotrema hababianum was identified as anticancer lichens on cervical cancer cells (Poornima et al. 2016). The marine sponge extract Cytarabine (Cyto star) has been used for non-Hodgkin lymphoma and Ecteinascidin, and Trabectedin (Yondelis) is the marine squirt extract being used in many cancer forms (Demain and Vaishnav 2011). The sea cucumber extract TBL-12 inhibits the proliferation, migration, and invasion of human prostate cancer cells by p38 mitogen-activated protein kinase and intrinsic caspase-mediated apoptosis pathway (Yuan et al. 2019). Some phytochemicals like curcumin and resveratrol have anticancer properties by targeting miR-34a, a cancer suppressor (Masika et al. 2016). Curcumin has the property of upregulating anticancer long noncoding RNA MEG-3 in hepatocellular carcinoma (Zamani et al. 2015). We know that particular phytochemical can effectively be anticancer to one or more cancer types; vinblastine has an anticancer property in breast cancer cells by suppressing miR-21a (Biersack 2016), miR-27b, miR-324-3p, miR-328, miR-148a, and miR-451 but above change is not observed in colon cancer cells (Zhu et al. 2008; Rodrigues et al. 2011). In some cases, cancer cells are resistant to chemotherapy and some are resistant to radiotherapy, this unfavorable resistance is favored by drug inactivation, drug target alteration, epithelial–mesenchymal transition, cell death inhibition, DNA damage repair, drug efflux, and by epigenetic regulation (Housman et al. 2014). Drug-resistant and radio-resistant cancers are obstacles to cancer treatment and made challenging incite to refractory tumor research.

17.6 An Overview of Micro-RNAs and Long-RNAs in Cancer Biology

As briefed in the introduction, the known micro-RNAs are 2300 and lnc-RNAs 172,216 transcripts with 96,308 genes according to “NONCODE,” but their functions are obscure particularly the lnc-RNAs have delicate gene modulation and have not been explored to date. Moreover, the long noncoding RNAs are involved in many biological processes like the development of embryos, embryonic stem cell differentiation, disease, and induced pluripotent stem cells (iPSCs) (Rao 2017). The long noncoding RNAs were dysregulated in various cancer, for example, aHIF, Air, anril, Car intergenic 10, GAS5, NGAS1-as-RNA, H19, MALAT, MEG3, NEAT1, PINC, Tsix and Zfast, etc. are encoded from first chromosome to almost all 22 pair of autosomal chromosome including X-chromosome (Spizzo et al. 2012) and ultimately long non-RNAs control all six cancer hallmarks proliferation, growth suppression, motility, immortality, angiogenesis, and viability of cancer phenotypes ( Schmitt and Chang 2016) (Fig. 17.2).

Fig. 17.2
A schematic representation of natural compounds influences cancer by non-coding R N As contains sensitizing refractory cancer, cancer invasion, cancer epigenetic modulations, inhibition of cancer metastasis, targeting multiple cancers, radio sensitization, and targeting cancer stem cells.

Major cancer-related modulations by natural compounds

Full size image

Some major classes of micro-RNAs like Piwi-interfering RNA have the ability in regulating cancer development and metastasis, despite the known 200,821 transcripts only 273 piRNAs were discovered out of which piR-36,743, piR-36,026, and piR-31,106 were dramatically upregulated and piR-34,736, piR-36,249, piR-35,407, piR-36,318, and piR-34,377 were significantly downregulated while among 100 identified piRNAs (Han et al. 2017). Another major group sno-RNA has an anticancer property in glioblastoma (Chen et al. 2015a) beside the evidence that sno-RNAs are involved in carcinogenesis, snoRNAs exhibit differential expression patterns in different human cancers and have the capability of regulating tumorigenesis, and metastasis, for example, U5O, h5sn2, RNU43, RNU44 are downregulated tumor suppressor in breast cancer and gliomas, besides upregulated sno-RNAs such as snoRD33, snoRD44, snoRD76 in non-small-cell lung cancer (Mannoor et al. 2012).

Initially micro RNA function is obscure but now its role in cancer is well understood and used for specific cancer diagnosis and prognosis. The circulating micro-RNAs and lnc-RNAs that are produced by exosomal release, exocytosis, micro-vesicles budding, necrosis, and apoptosis are used in cancer diagnosis. For example, miR-21 and miR-210 in B-cell lymphoma; miRNA-141 in prostate cancer; miR-25 and miRN-223 in lung cancer; miR-21, miR-92, miR-93, miR-126, and miR-29a ovarian in cancer; miR-17-3p and miR-92 in colorectal cancer; miR-92a in acute leukemia; miR-210, miR-155, and miR-196a in pancreatic cancer; miR-184 squamous cell carcinoma; miR-500 in hepatocellular carcinoma has been shown to be upregulated in cancer cells and can be detectable in circulating blood (Hamam et al. 2017). RNAs H19, MALAT1, ANRIL, HIFA-AS2, and HOTAIR are upregulated in breast cancer patients, can be detectable in uirne or plasma and serum (Yu et al. 2018).

17.7 Natural Compounds Have Anticancer Properties by Targeting Micro-RNA Etoposide

Etoposide is a natural compound derived from Podophyllum peltatum, and its semisynthetic form is a glycosylated podophyllotoxin with d-glucose. Etoposide is a topoisomerase inhibitor, and it is a known chemotherapeutic medication for testicular cancer, lung cancer Hodgkin’s lymphoma, and many more (Anonymous 2011; Stuart et al. 2008). Human osteosarcoma cell lines, wild-type (wt) p53 U2-OS, mutant-p53 MG63, show better sensitivity to etoposide than p53-deficient MG63 and Saos-2 cells. The wild-type (wt) p53 U2-OS, mutant-p53 MG63 showed increased levels of unmethylated miR-34a, reduced expression of CDK4, and cell cycle arrest in the G1 phase (Novello et al. 2014). Another study by Kollinerová et al. shows miR-29b potentiates etoposide toxicity to Hela cells by downregulating the Mcl-1 protein (Kollinerová et al. 2017), Mcl-1 is an anti-apoptotic protein belonging to the Bcl-2 family (Xiang et al. 2018).

MCF-7 cells were sensitized to etoposide by overexpressed miR-195, miR-24-2, and miR-365-2 and showed decreased levels of Bcl-2 protein (Singh and Saini 2012), drugs regulating these miRNAs may be helpful in breaking resistance. The miR-195 arrests cancer cell proliferation, invasiveness, and migration of MCF-7 and MDA-MB-31 cells (Singh et al. 2015). miR-24-2 exhibit anti-apoptotic effect by targeting Bcl-2 in cancer cells (Srivastava et al. 2011), and miR-365 downregulated in hepatocellular carcinoma and stomach adenocarcinoma act as a tumor suppressor (Zhou and Liu 2013). Thus, these miRNAs can be used as therapeutic drug to treat various forms of cancers.

Hypoxia down-regulated the expression of miR-196b, which was induced by etoposide. The miR-196b overexpression increased the etoposide-induced apoptosis and reversed the protection of cell death observed under hypoxia. IGF2BP1 is the potential target of miR-196b. Indeed, miR-196b overexpression decreased IGF2BP1 RNA expression and protein level. The IGF2BP1 down-regulation by either miR-196b or IGF2BP1 siRNA led to an increase in apoptosis and a decrease in cell viability and proliferation in normal culture conditions (Rebucci et al. 2015). IGF2BP1 is essential in embryogenesis and tumor development (Huang et al. 2018a), while the miR-196b has a versatile antitumor role in chronic myeloid leukemia and pancreatic cancer cells through BCR-ABL1-HOXA9 and CADM1, respectively (Liu et al. 2013a; Wang and Zhou 2017). CADM1 is a cell adhesion molecule which is involved in metastasis of cancer cells (Wikman and Westphal 2014) (Table 17.2).

Table 17.2 Micro-RNA regulation in cancer by natural compounds
Full size table

Etoposide is a refractory cancer drug for testicular cancer and is being used for various cancer, small cell carcinomas (multiple sites), adrenal cancer, gynecological cancers (GTD, others), sarcomas (Wilms tumor, soft tissue, Ewing’s), CNS cancers, thymoma, Merkel cell, leukemias (CCO Formulary 2017). Furthermore, etoposide in being under clinical trial in a randomized phase II study of cisplatin and etoposide in combination with either Hedgehog inhibitor GDC-0449 or IGF-1R MOAB IMC-A12 for patients with extensive stage cancer, and these novel miRNAs could extend etoposide research in other cancer with evidence (Anonymous 2019a). Hedgehog signal involved in cancer stem cells and self-renewal (Carballo 2018).

17.7.1 Anacardic Acid

Anacardic acids are phenolic lipids (6-pentadecyl salicylic acid, 6-(8(Z), 11(Z), 14-pentadecatrienyl) salicylic acid, 6-(8,11,14-pentadecatrienyl)salicylic acid, 6-nonadecyl salicylic acid) derived from Anacardium occidentale (Cashew nuts), and Semecarpus anacardium (Marking nut) belongs to Anacardiaceae (Anonymous 2019b) (Rahman 2018). The marking nut plant is one of the medicinal plants prevalent in India, the plant has been described in the Siddha and Ayurveda system of alternative medicine literature (Murugesa Mudaliar 2003). Anacardic acid from cashew nut shells stimulates neutrophil extracellular trap (NET) that is responsible for bactericidal and complement select direct antimicrobial activities of the compound (Hollands et al. 2016). The miR-378g, miR-509, miR-513b-5p, miR-548j upregulated and Let-7a-2-3p, miR-378j, miR-520d-5b, miR-1976, miR-551b-5p and many more were downregulated in MCF-7 cells, in the same they have found miR-378f, miR-1257, miR-1298-5p, miR-1304-5p were upregulated and miR-23b-5p, miR-141-3p miR-499a-5p, miR-1247-5p, miR-4284 were downregulated in MDA-MB-231 cells (Deng et al. 2013). High miR-378 promotes cancer stem cell (CSC) properties, increased cell survival, and colony formation correlate with increased SOX2 (Deng et al. 2013) miR-548J functions as a metastasis promoter in breast cancer cells (Zhan et al. 2016), Let-7a-2-3p decreased expression with breast tumor grade and upregulated KEGG pathway targets have roles in cancer-related pathways, including cycle (MCM2), Jak-STAT (SOCS1), MAPK (STMN1), PPAR signaling (ME1) (Oztemur et al. 2015) and metastatic breast cancer cells in patient’s bone marrow had increased expression of miR-23b-5p (Radde et al. 2016). Anacardic acid is proven to be antioxidant, anticancer, anti-inflammatory, antimicrobial, anti-obesity, and insecticidal (Hemshekhar et al. 2012), but human trial are not yet been studied, except preclinical study in which anacardic acids from Anacardium occidentale (Cashew nuts) gives better response in lung damage induced by exposure to diesel exhaust particles in mice (Carvalho et al. 2013).

17.7.2 Chrysin

Chrysin is a flavone sub-class of flavonoid and it is present in honey, propolis, passionflower (Passiflora caerulea, Passiflora incarnata),, and Indian trumpet flower (Oroxylum indicum) (family: Bignoniaceae). Oroxylum indicum (trumpet flower) is distributed throughout India, and its medicinal properties were enshrined in the Ayurveda literature (Deka et al. 2013). In multiple studies, miR-34a, miR-22, miR-126, miR-18a, miR-21, miR-221, miR-9, and Let-7a upregulated by nano-encapsulated chrysin in the gastric cancer cell (Mohammadian et al. 2015, 2016a, b, 2017a, b). Interestingly chrysin upregulated three tumorigenic miRNAs (miR-21, miR-221, miR-18), miR-18a and miR-25-106b in HCC was associated with poor survival in clinical samples and promoted proliferation in HCC cell lines (Masika et al. 2016; Sanchez-Mejias et al. 2019). Moreover its tumor suppressive property (miR-34a, miR-22, miR-9, miR-26, and Let-7a) against other colon and breast cancer cells were investigated (Yang et al. 2015a). The miR-34a is a known tumor suppressor, and the other miR-9 act as a tumor suppressor shown in a study in which animal xenograft assays evidence that miR-9 acts as a tumor suppressor by targeting CXCR4 in vivo (Xiong et al. 2018) and the miR-26 acting as a tumor suppressor in bladder tumor, breast cancer, oral squamous cell carcinoma, anaplastic carcinomas by EZH2 as a target with oncogenic in glioma by PTEN as a target (Gao and Liu 2011). Chrysin may target gastric cancer stem cells by miRNA-34a and Let-7a (Table 17.3).

Table 17.3 Long noncoding RNA regulation in cancer by natural compounds
Full size table

The protective effects of chrysin evident in toxic-agent (methotrexate, cisplatin, ethanol, etc.) induced toxicity amelioration, through various mechanisms in different tissues including the brain, heart, liver, kidney, lung, etc. (Samarghandian et al. 2017). Chrysin possesses potent neuroprotective effects and suppresses neuroinflammation. In addition, it improves cognitive decline by possessing anti-amyloidogenic and neurotrophic effects, and offered neuroprotective effect in experimental models of depression and epilepsy (Nabavi et al. 2015). Human clinical trials have not been reported yet.

17.7.3 Paclitaxel

Paclitaxel (Taxol) is derived from the Pacific yew tree, Taxus brevifolia. The samples were collected by USDA botanist Arthur Barclay on his expedition in 1962, and its anticancer property was explored by NCI (National Cancer Institute of U.S) Taxol (generic name paclitaxel) which is a popularly known drug that is approved by the Food and Drug Administration for the treatment of ovarian, breast, and lung cancer, as well as Kaposi’s sarcoma. It is also used to treat gastroesophageal, endometrial, cervical, prostate, and head and neck cancers, in addition to sarcoma, lymphoma, and more (Weaver 2014).

The miR-29c regulates resistance to paclitaxel in nasopharyngeal cancer, by targeting ITGB1 (Huang et al. 2019), and miR-29c suppresses invasion and metastasis by targeting TIAM1 in nasopharyngeal carcinoma (Liu et al. 2013b). Brown seaweed Fucoidan inhibited human breast cancer progression by upregulating microRNA miR-29c and miRNA-29a is being upregulated by curcumin hepatocellular carcinoma (Wu et al. 2016), thus fucoidan or curcumin in future research with nasopharyngeal carcinoma could break paclitaxel resistance.

The lnc-RNA LINC01118 modulates paclitaxel resistance of epithelial ovarian cancer by regulating miR-134/ABCC1 (Shi and Wang 2018), (ABCC1/multidrug resistance-associated protein 1 (MRP1) transports (Munoz et al. 2007). The miR-134 clusters were downregulated in paclitaxel-resistant cancer cells than the sensitive cells, and the miR-17-92 cluster was inversely expressed in ovarian cancer (Zhu et al. 2016), and in a study the miR-134 can suppressor tumor by regulating suppressing EGFR and PI3K signaling in colorectal cancer (El-Daly et al. 2016). In osteosarcoma, miR-134 shows a tumor suppressive role by attenuating the expression of VEGFA and VEGR 1 (Zhang et al. 2018), miRNA-134 inhibits EMT of small cell lung cancer (Li et al. 2012) miRNA-134 could be a target of paclitaxel in cancer cells. In another case, the miR-22 expression increases chemosensitivity to paclitaxel in MCF-7 cells and it has been downregulated in breast cancer (Song et al. 2018).

The exosomal delivery of miR-155-5p converts the paclitaxel-resistant gastric cancer cells into paclitaxel sensitive cells and it could be a future target of resistance (Wang et al. 2019). MicroRNA-34a reduces paclitaxel resistance in prostate cancer cells by suppression of the JAG1/Notch1 axis (Liu et al. 2018a) we know that miR-34a is being upregulated by curcumin, chrysin, resveratrol in other cancer, further work in combination with curcumin, chrysin, resveratrol, and paclitaxel may break the resistance of prostate cancer cells to paclitaxel. Paclitaxel is being under clinical trial in refractory or relapsed solid tumors (Anonymous 2017a).

17.7.4 Glycyrrhetenic Acid

Glycyrrhetinic acid (Enoxolone) is mainly isolated from Glycyrrhiza glabra linn a tropical shrub that belongs to Leguminosae and used in Siddha and Ayurveda systems of medicine for thousands of years (Murugesa Mudaliar 2003). Glycyrrhetinic acid has several medical properties like antihyperglycemic, antiallergic, anti-inflammatory, antiviral, anticancer, and expectorant (Roshan et al. 2012). The miR-149-3p upregulation and Wnt-1 signaling by 18β-Glycyrrhetinic acid suppress gastric cancer in vivo study (Cao et al. 2016). The miR-149-3p shows to be tumor suppression (He et al. 2018) in dioscin-induced upregulation of miR-149-3p trough targeting Bax, Apaf-1, cleaved caspase-3/9, cleaved PARP, suppressing Bcl-2 levels in ASPC-1 and PANC-1 cell xenografts (Si et al. 2017), and tumor suppressive property of miR-149-3p is being reflected in bladder cancer cells by S100A4 (Yang et al. 2017a). In other cancer forms like bladder (BLCA), breast (BRCA), lung (LUSC), endometrial (UCEC), and prostate (PRAD), the miR-149-3p is differentially expressed and favors tumor progression, the miR-149 family miR-149-5p or miR-149-3p plays dual roles in the proliferation and apoptosis of various tumors (Bellazzo et al. 2018). Glycyrrhetinic acid is a generic drug in the name of enoxolone and is categorized as cicatrizant, an anti-inflammatory agent, drug acting on the gastrointestinal system (Anonymous 2017b).

17.7.5 Marine Metabolite 1386A

1386A is a metabolite of mangrove marine fungi indigenous to the South China Sea. Tang et al. study on MCF-7 cells shows cytotoxicity and influencing ambivalently both tumor-suppressing and oncogenic micro-RNAs. Let-7, miR-15, miR-16 were downregulated and miR-27a, miR-21, miR-7, miR-663 were upregulated by marine metabolite 1386A in MCF-7 cells (Tang et al. 2012a). It has been reported that miR-7 is a potential tumor suppressor in breast cancer, and it influences the CSCs of breast cancer cells. The miR-663 targets TGFβ1 transcripts, which are associated with the invasion and metastasis of gastric cancer through the activation of the TGFβR1-ALK5/SMAD3 pathway. In the same study, some are dysregulated, miR-320 family, miR-125b, miR-638. The miR-320a inhibits breast cancer cell proliferation and migration (Wang et al. 2015), and miR-320d suppresses the progression of breast cancer via lncRNA HNF1A-AS1 regulation and SOX4 inhibition (Shi et al. 2022). The overexpression of miR-125b is sensitizing paclitaxel-resistant breast cancer cells to paclitaxel by targeting Sema4C (Yang et al. 2014), in another case miR-125b promoted metastasis of MCF-7 and MDA-MB-231 cell (Tang et al. 2012b). The miR-125a-3p and miR-125a-5p show reduced expression in non-small-cell lung cancer and have inverse effects on the invasion and migration of lung cancer cells A549 and SPC-A-1 (Jiang et al. 2010). The miRNA-638 is the enhancer of autophagy in malignant phenotypes cells via directly suppressing DACT3 (Ren et al. 2017) but miR-638 was upregulated by its metabolite 1386A to enhance the autophagy. Even though many oncogenic micro-RNAs were upregulated and downregulated tumor suppressors, the marine metabolite 1386A reduced cell proliferation and arrested the growth of MCF-7 cells in vitro.

17.8 Natural Compounds Have Anticancer Properties by Targeting Long Noncoding RNA

Only a few natural compounds have studied for the anticancer action with long noncoding RNA regulation, because of its ambiguous functionality through 172,216 lns-RNAs transcripts were reported in humans. Almost 12 natural compounds influence cancer by oncogenic lnc-RNAs HOTAIR, ROR, MALAT-1, and H19, and enhancing cancer suppressors GAS5 and MEG3 (Mishra et al. 2019).

17.8.1 Curcumin

Curcumin is one of the multifunctional 134 acted as a tumor suppressor by regulating suppressing EGFR and PI3K signaling in colorectal cancer (El-Daly et al. 2016). In osteosarcoma, miR-134 shows a tumor suppressive role by attenuating the expression of VEGFA and VEGR 1 (Zhang et al. 2018), miRNA-134 inhibits EMT of small cell lung cancer (Li et al. 2012), miRNA-134 could be a target of paclitaxel in cancer cells. In another case, the miR-22 expression increases chemosensitivity to paclitaxel in MCF-7 cells and it has been downregulated in breast cancer (Song et al. 2018).

The exosomal delivery of miR-155-5p converts the paclitaxel-resistant gastric cancer cells into paclitaxel sensitive cells and it could be a future target of resistance (Wang et al. 2019). MicroRNA-34a reduces paclitaxel resistance in prostate cancer cells by suppression of the JAG1/Notch1 axis (Liu et al. 2018b) we know that miR-34a is being upregulated by curcumin, chrysin, resveratrol in other cancer, further work in combination with curcumin, chrysin, resveratrol, and paclitaxel may break the resistance of prostate cancer cells to paclitaxel. Paclitaxel is being under clinical trial in refractory or relapsed solid tumors (Anonymous 2017b).

17.8.2 Glycyrrhetenic Acid

Glycyrrhetinic acid (Enoxolone) is mainly isolated from Glycyrrhiza glabra linn a tropical shrub that belongs to Leguminosae and used in Siddha and Ayurveda systems of medicine for thousands of years (Murugesa Mudaliar 2003). Glycyrrhetinic acid has several medical properties like antihyperglycemic, antiallergic, anti-inflammatory, antiviral, anticancer, and expectorant (Roshan et al. 2012). The miR-149-3p upregulation and Wnt-1 signaling by 18β-Glycyrrhetinic acid suppress gastric cancer in vivo study (Cao et al. 2016). The miR-149-3p shows to be tumor suppression (He et al. 2018) in dioscin-induced upregulation of miR-149-3p trough targeting Bax, Apaf-1, cleaved caspase-3/9, cleaved PARP, suppressing Bcl-2 levels in ASPC-1 and PANC-1 cell xenografts (Si et al. 2017), and tumor suppressive property of miR-149-3p is being reflected in bladder cancer cells by S100A4 (Yang et al. 2017a). In other cancer forms like bladder (BLCA), breast (BRCA), lung (LUSC), endometrial (UCEC), and prostate (PRAD), the miR-149-3p is differentially expressed and favors tumor progression. The miR-149 family miR-149-5p or miR-149-3p plays dual roles in the proliferation and apoptosis of various tumors (Bellazzo et al. 2018). Glycyrrhetinic acid is a generic drug in the name of enoxolone and is categorized as cicatrizant, an anti-inflammatory agent, drug acting on the gastrointestinal system (Anonymous 2017b).

17.8.3 Marine Metabolite 1386A

1386A is a metabolite of mangrove marine fungi indigenous to the South China Sea. Tang et al. study on MCF-7 cells shows cytotoxicity and influencing ambivalently both tumor-suppressing and oncogenic micro-RNAs. Let-7, miR-15, miR-16 were reduced in expression, and miR-27a, miR-21, miR-7, miR-663 were upregulated by marine metabolite 1386A in MCF-7 cells (Tang et al. 2012a). It has been reported that miR-7 is a tumor suppressor in breast cancer, and it influences the CSCs of breast cancer cells. The miR-663 targets TGFβ1 transcripts, which are associated with the invasion and metastasis of gastric cancer through the activation of the TGFβR1-ALK5/SMAD3 pathway. In the same study, some are dysregulated, miR-320 family, miR-125b, miR-638. The miR-320a inhibits breast cancer cell proliferation and migration (Wang et al. 2015) and miR-320d suppresses the progression of breast cancer via lncRNA HNF1A-AS1 regulation and SOX4 inhibition (Shi et al. 2022). The overexpression of miR-125b is sensitizing paclitaxel-resistant breast cancer cells to paclitaxel by targeting Sema4C (Yang et al. 2014), in another case miR-125b promoted metastasis of MCF-7 and MDA-MB-231 cell (Tang et al. 2012b). The miR-125a-3p and miR-125a-5p expression is reduced in non-small-cell lung cancer and has inverse effects on the invasion and migration of lung cancer cells A549 and SPC-A-1 (Jiang et al. 2010). The miRNA-638 is the enhancer of autophagy in malignant phenotypes cells via directly suppressing DACT3 (Ren et al. 2017) but miR-638 was upregulated by its metabolite 1386A to enhance the autophagy. Even though many oncogenic micro-RNAs were upregulated and downregulated tumor suppressors, the marine metabolite 1386A reduced cell proliferation and arrested the growth of MCF-7 cells in vitro.

17.9 Natural Compounds Have Anticancer Properties by Targeting Long Noncoding RNA

Only a few natural compounds have studied for the anticancer action with long noncoding RNA regulation, because of its ambiguous functionality through 172,216 lns-RNAs transcripts were reported in humans. Almost 12 natural compounds influence cancer by oncogenic lnc-RNAs HOTAIR, ROR, MALAT-1, and H19 and enhance cancer suppressors GAS5 and MEG3 (Mishra et al. 2019).

Alkaloids isolated from the rhizome of Curcuma longa and belongs to Zingiberaceae. The rhizome is being used as a medication for versatile medical purposes like antibacterial, antiseptic, anthelminthic, sprain, chicken pox, and many more conditions by traditional practitioners in India (Deb et al. 2013; Murugesa Mudaliar 2003). Curcumin is one of the explored alkaloids with studies on both micro-RNAs and long-RNAs. MEG-3 upregulated miR-29a and miRAQ20-186 in hepatocellular carcinoma cells (Zamani et al. 2015). MEG-3 is a known tumor suppressor, i.e. suppression of pancreatic cancer by PI3K protein (Gu et al. 2017), controlling proliferation and metastasis of gastric cancer via p53 signaling pathway (Wei and Wang 2017) and tumor suppressive role in clinically non-functioning adenomas (neoplasia of gonadotrophic pituitary gland) by p53, BRCA1 and PTEN (Zhou et al. 2012). In the same case, curcumin concurrently upregulates the expression of tumor suppressors, miR-29a and mir-186. The miR-29a has tumor suppressor activity in pancreatic cancer (Trehoux et al. 2015), metastasis of pancreatic cancer, and gastric cancer (miR-29a-3p) by targeting MUC1, caveolin-2, and CDK (2, 4, 6), respectively (Liang et al. 2018a; Zhao et al. 2015), along with miR-186 which have tumor suppressive property in prostate cancer (Hua et al. 2016), prostate cancer metastasis (miR-186-5p), (Jones et al. 2018), and bladder cancer (Yao et al. 2015) by GOLPH3, AKAP12, and NSBP1 target, respectively. Curcumin could modulate miRNAs and in-RNAs simultaneously by MEG-3, miR-29a, and miR-186 on the hepatocellular carcinoma.

Lnc-RNAs AF086415, AK095147, RP1-179N16.3, MUDENG, AK056098, and AK294004 reversed by curcumin in nasopharyngeal carcinoma (NPC) which were differentially expressed in the radioresistance cell of NPC (Wang et al. 2014). Radio resistance is one of the drawbacks of cancer treatment by radiation therapy, curcumin can be the best drug in sensitizing cancer cells to radiation by the above lnc-RNA by reversing expression levels. Curcumin presumptuously used in India and Asia has potential anticancer properties in several cancer, and its first phase-1 human trial was reported by Cheng and colleagues 2001 (Hsu and Cheng 2007). Now curcumin, under clinical trial in memory effect (in persons with genetic risk of Alzheimer’s disease) (phase-2) (Anonymous 2007), pancreatic cancer (Adenocarcinoma) (phase-2) (Anonymous 2013) and primary sclerosing cholangitis (phase-2) assessed by reducing ALP (alkaline phosphatase) by 40% (Anonymous 2014a) (Table 17.3).

17.9.1 Rutin

Rutin is flavonol glycoside present in many plants tobacco, buckwheat, viola, and many more (Anonymous 2015). Rutin upregulates 144 long noncoding RNAs (HSP90AA2P, AP000866.6, AC125257.1, GAS5, SLC25A24P2, ANKRD20A11P) and downregulates 54 long-noncoding RNAs (AL390038.1, LINC01126, LINC01106, SIAH2-AS1, AP001972.5, AL132800.1) in human SW480 colorectal cancer cells, in which reduced cell metabolism with a cell growth arrest at sub-G1 phase (Nasri Nasrabadi et al. 2019). Interestingly GAS5 is one of the tumor suppressor lnc-RNA which was upregulated by Rutin in SW480 colorectal cancer cells and inhibits cell growth, in other studies GAS5 showed tumor suppressive properties in breast cancer, colorectal cancer, ovarian cancer, and prostate cancer by acting through various targets. The clinical trial status of Rutin has interestingly been studied in autism spectrum disorders by reducing inflammatory mediators from mast cells and IL-6-induced autism-like behavioral deficits (Anonymous 2023).

17.9.2 Doxorubicin

Doxorubicin is derived from Streptomyces peucetius var. caesius, a bacterial product (Nakano et al. 2015) and used for solid tumors of the ovary, uterus, breast, osteosarcoma, esophagus, stomach, liver, childhood solid tumors, and hematological cancer forms (Carvalho et al. 2009). Doxorubicin resistant OS (osteosarcoma) cells can be sensitized to Dox by upregulating lnc-RNA CTA and competitively downregulating miR-210 in nude mice (Wang et al. 2017a). Exogenous overexpression of miR-210-3p inhibited the proliferation, migration and invasion of bladder cancer cells in vitro. In addition, the nude mouse xenograft model showed that miR-210-3p over-expressing inhibited bladder cancer growth and liver metastasis whereas silencing miR-210-3p caused an opposite outcome, which is mainly regulated by targeting fibroblast growth factor receptor-like 1 (FGFRL1) (Yang et al. 2017b). The miR-210 favors apoptosis which was associated with an upregulation of pro-apoptotic Bim expression and enhanced Caspase 2 in colorectal cancer (Tagscherer et al. 2016), and miR-210 knockdown promotes cell proliferation by upregulating E2F3 expression, thereby promoting the progression of pancreatic cancer (Sun et al. 2018) hence miR-210 is a tumor suppressor in all other cancer forms, but in OS miR-210 promotes cancer progression and development and sensitizing OS cells to doxorubicin by lnc-RNA CTA. Doxorubicin is being clinically trailed for 141 different conditions in European Union mostly in ovarian cancer, hepatocellular carcinoma, breast cancer, and refractory cancer (Anonymous 2018). This randomized phase III trial studies doxorubicin hydrochloride, cyclophosphamide, and paclitaxel to see how well they work with or without bevacizumab in treating patients with cancer that has spread to the lymph nodes (lymph node-positive) or cancer that has not spread to the lymph nodes but is at high risk for returning (high-risk, lymph node-negative breast cancer) (https://clinicaltrials.gov/ct2/show/NCT00433511) (Anonymous 2017c).

17.9.3 Paclitaxel and Docetaxel

lnc-RNA LINC01118 modulates paclitaxel resistance of epithelial ovarian cancer by regulating miR-134/ABCC1. The lnc-RNAs LINC01118 could facilitate cancer progression and metastasis of epithelial ovarian cancer and can be chemoresistant to paclitaxel by targeting miR-134 (downregulated) and ABCC1 protein (upregulated) (multidrug resistant transporters, C branch of ABC transporters). The miR-134 clusters were downregulated in paclitaxel-resistant cancer cells than the sensitive cells, miR-17-92 clusters were inversely expressed. miR-134 acts as a tumor suppressor by regulating suppressing EGFR and PI3K signaling in colorectal cancer. In other studies, miR-134 shows a tumor suppressive role in osteosarcoma by attenuating the expression of VEGFA, and VEGR 1, along with inhibition of epithelial to mesenchymal transition by targeting FOXM1 in non-small-cell lung cancer cells, miRNA-134 acts as anti-CSCs in glioblastoma. The tumor suppressor miR-134 being downregulated by lnc-RNA LINC01118 and sensitizing to paclitaxel in epithelial ovarian cancer is inversely related to another case indeed.

Docetaxel (Taxotere®), a semisynthetic compound analogous to paclitaxel (Taxol®) varies by two positions in chemical structure, docetaxel has significant activity in breast, non-small-cell lung, ovarian, and head, and neck cancers cell cycle arrest at G2/M, apoptosis, and cytotoxicity by promoting microtubule polymerization (Clarke and Rivory 1999). Docetaxel resistance is created by lnc-RNAs NONHSAG096479.1, NONHSAG048134.2, NONHSAG048135.2, NONHSAG048143.2, and NONHSAG048143.2 by which the ABCB1 transporters were the enhanced expression. ABCB1 is reported in drug-resistant cancer forms (Huang et al. 2018b).

17.9.4 Magnolol

Magnolol is tree bark and stem extract of Magnolia officinalis, a Chinese plant belonging to the Magnoliaceae family, and it is used for various medical conditions by traditional healers in China. Magnolol and its methoxylated 2-O-methylmagnolol (MM1) compound have the property of upregulating GAS5 (growth arrest-specific 5) in skin cancer cells in vitro and in vivo as well and they showed MM1 is more effective than Magnolol. MM1 has upregulated GAS5 twice the magnolol in A375 cells and the caspase 3 activity results that MM1 is more potent than magnolol in in vivo mouse experiment (Wang et al. 2017b). While GAS5 is identified as a tumor suppressor, in breast cancer cells GAS5 is downregulated, and it regulates autophagy by acting as ceRNA to miR23a via ATG3 both in vivo and in vitro (Gu et al. 2018), GAS5 is downregulated in colorectal cancer and pancreatic cancer and GAS5 overexpression could inhibit cancer cell proliferation and reduce EMT, metastasis by targeting miR-182-5p/FOXO3a axis (Cheng et al. 2018) and miR-221/SOCS3 (Liu et al. 2018a), respectively. The GAS5 alternatively suppresses ovarian cancer cells by inflammasome formation, and it has been hindered by downregulation of IL-1, IL-10, ASC, caspase 1, IL-1β, and IL-18 which are involved in pyroptosis pathways (Li et al. 2018). But GAS5 family lnc-RNA GAS5-007 is an oncogenic function in prostate cancer, and its function is controlled by androgen treatment in vitro (Zhang et al. 2017a).

Magnolol proven in the prevention and treatment of more than 15 cancers (Ranaware et al. 2018). Magnolol can prevent atherosclerosis and vessel restenosis, attenuate post-angioplasty restenosis, promote vessel dilation, and prevent platelet aggregation and thrombus formation (Ho and Hong 2012). Magnolol cloud is an abusable compound of GABA-ergic/cannabimimetic activities, by its metabolites tetrahydromagnolol and honokiol (Schifano et al. 2017).

17.9.5 Sulforaphane

Sulforaphane is isolated from broccoli (Brassica oleracea var. italica), a common vegetable in daily use. Sulforaphane has the property of tumor suppression in prostate cancer cell PC-3 cells, by a novel mechanism through lnc-RNAs LINC01351, LINC00883, LINC01059, and LINC01116 with inversely regulated genes GAPDH, MAP 1LC3B2 (autophagy), and H2AFY to the above lnc-RNAs by sulforaphane treatment. LINC01351, LINC00883, LINC01059, and LINC01116 were upregulated in prostate cancer cells and they are significantly reduced by sulforaphane treatment (Beaver et al. 2017). The LINC01116 enhanced tumor progressive and overexpressed in another tumor form, epithelial ovarian cancer (Fang et al. 2018), and non-small-cell lung cancer via the caspase-mediated pathway (Liang et al. 2018b), but in breast cancer, it acts like an endogenous sponge for miR-145 and upregulates ESR1 (estrogen receptor 1) (Hu et al. 2018). Transplacental carcinogenesis with Dibenzo[def,p]chrysene (DBC): Timing of maternal exposures determines target tissue response in offspring (Shorey et al. 2012). They are ubiquitous and formed as a by-product of natural and anthropogenic combustion processes.

Sulforaphane has the potency to provide chemoprotection to the fetus transplacentally. The lnc-RNA MSUR-1 upregulation by sulforaphane is mediated by Nrf2 (Nuclear Factor Erythroid-2-Related Factor) (Patel et al. 2018). Sulforaphane has clinically trailed in the past decade, in recurrent prostate cancer (2018) (Anonymous 2018), COPD (Anonymous 2017a), breast cancer (Anonymous 2014b), and prostate cancer (Anonymous 2017b) by organizations from Australia and USA and have reached phase-2 clinical trials. In 2015, sulforaphane-rich broccoli sprout extracts in men with recurrent prostate cancer were clinically trailed in phase 2 (Alumkal et al. 2015).

17.10 Natural Compounds Attenuate Cancer Stem Cells by Targeting Noncoding RNAs

In cancer biology treatment, neither chemotherapy nor surgical or radiotherapy may cause a relapse of cancer a few years later cancer treatment probably by cancer stem cells (Mitra et al. 2015). The self-renewal of the cancer stem cells in various cancer forms is regulated by micro-RNAs as well as by long-noncoding RNAs. Firstly the micro-RNA contribution for cancer stem cells and self-renewal are, in breast cancer Let-7, miR-200 family, miR-34c, miR-16 are downregulated with upregulated miR-181 and miR-495; in prostate cancer, miRNA-34a and miR-Let-7b are downregulated with miR-143 upregulation; in glioblastoma miR-451 and miR-128 are downregulated; in hepatocellular carcinoma miR-181 family and miR-17 and miR-92 are upregulated (Ghosh and Mallick 2014); in colorectal cancer miR-349, miR-200b/c, miR-203, miR-137 are downregulated along with upregulated miR-221 (Mukohyama et al. 2017); in lung cancer, miR-27a is upregulated; in leukemia miR-22 and miR-126 is upregulated (Garofalo and Croce 2015), the downregulated miRNAs are cancer stem cell suppressive nature and upregulated are promoted self-renewal of CSCs.

Secondly, the lnc-RNAs influencing CSCs phenotype is, in gastric cancer ROR is upregulated; in colorectal cancer, HOTAIR is upregulated; in breast cancer, H19 is upregulated; in liver cancer, UCA1 is upregulated, the upregulated lnc-RNAs are having the potency of maintaining stem cell-like property in respective cancer cells (Chen et al. 2017). Piperine and salinomycin reduce CSC potency by the Wnt pathway, celastrol and resveratrol arrest CSC property by notch, nanog (Burnett et al. 2012), and OCT4 pathway, sulforaphane acts through HSP90 and AKT pathways, and curcumin controls CSCs property by STAT3 phosphorylation in ALDH+/CD133+ colon CSCs (Taylor and Jabbarzadeh 2017).

Curcumin, chrysin, etoposide, resveratrol, and Boswellic acid may suppress cancer stem cells in respective cancer because miR-34a is reported as CSCs suppressive properties in more than three cancer types (breast cancer, prostate cancer, glioblastoma, and colorectal cancer and osteosarcoma) (Table 17.4). Let-7 family is reported as CSCs suppressive in prostate cancer and breast cancer, Let-7 is being upregulated by curcumin, chrysin, and boswellic acid, in gastric cancer and colorectal cancer (Table 17.4). The anacardic acid shows ambivalent regulation of the miRNA-378 family in MCF-7 cells and MDA-MB-231 cells (in Table 17.4). Boswellic acid and curcumin may control colorectal in a better way by upregulating CSCs suppressive miR-34a and Let-7 family and downregulating miR-27a a CSCs enhancer. In future research, the specific role of natural compounds respective to micro-RNA in CSCs suppression will be revealed. Natural products or extracts from the natural source (Fig. 17.3) could be a cure by targeting cancer stem cells.

Table 17.4 Natural compounds targeting noncoding RNAs may have controlling cancer stem cells
Full size table
Fig. 17.3
A chart exhibits natural compounds that putatively could control cancer stem cells by targeting m i- R N As. The natural compounds and cancer stem cells interconnect with cancer stem cell inhibition through long non coding R N As and micro R N As.

The schematic diagram of natural compound in controlling cancer stem cells

Full size image

17.11 Future Prospective

Natural compounds from natural sources (nutraceuticals) and its chemical extracts could be a promising cure for neural diseases such as Alzheimer’s disease, Parkinson’s disease, glioblastoma, neuroinflammation, etc.

The anticancer natural compounds are sourced from several plants, fungi, algae, and animals that are being anticancer by a plethora of cellular mechanisms. The recent studies involving the in vitro, in vivo, preclinical, and clinical trials of natural compounds with the anticancer property are providing a less toxic effect and could be antitoxic to various toxic agents. Natural compounds are manifest to be anticancer through modulations of noncoding RNAs by enhancing cancer apoptotic pathways by caspase, PTEN, Bcl-2, Mcl-1, etc. Natural compounds can target multiple cancer, curcumin is anticancer in breast cancer, prostate cancer, colon cancer, and more. Natural compounds can inhibit cancer metastasis through modulating miRNAs and lnc-RNAs by attenuating the epithelial–mesenchymal transition of the cancer cells. They provide epigenetic modulation in cancer, curcumin alters methylation (DNMT3A, B, and DNMT1 inhibition) of MEG3 in hepatocellular carcinoma and more than 20 natural compounds are proven to epigenetic modulators in MCF-7 cells by DNA methylation, histone H3K9 and K27 studied (Vidakovic et al. 2018).

Drug-resistant cancer can be sensitized to natural compounds by miRNAs, such examples are miR34a in paclitaxel-prostate cancer resistance, LINC01118 in paclitaxel-epithelial ovarian cancer resistance, miR-29b in doxorubicin-HeLa cell resistance, and many more in different cancer. Extended research in refractory cancers with specific miRNA and in-RNAs targeting compounds could be helpful in the future.

Providing cancer cure, the most appropriate words can be entitled to natural compounds by targeting cancer stem cells. The stemness of the cancer cells is insidious behind recurrent cancer or cancer relapse, indeed after surgical resection of cancer mass. Natural compounds can act as a double-edged sword, in regeneration (neurite formation, bone regeneration (Tohda et al. 2005) and ameliorates myocardial infarction (Kim et al. 2016) and degeneration of cancer mass by targeting miR-34a, Let-7 (putatively) in various cancer and ROR (prostate cancer) and attenuates cancer stem cells. Natural compounds could be clinically approved, a highly dynamic anticancer drugs.