Keywords

20.1 Phytochemicals and Nano-phytochemicals as Potent Anticancer Agents

Cancer remains a universal destructive disease and the second most common cause of death in humans. Approximately 7.6 million mortalities per year are attributed to cancer. Developing nations are facing more cancer incidence and now represent about 60% of the deaths (Siegel et al. 2017). The World Health Organization has predicted that about 15 million new incidences of cancer will emerge globally in 2020. Anticancer activity is the consequence of natural or synthetic compounds to reverse, repress, or check the development of cancer. As the present radiotherapy and chemotherapy treatments do not distinguish normal cells from cancer cells and thus can cause severe side effects, researchers and the pharmaceutical industry are concerned to develop a smart drug that can cure this destructive disease without affecting normal healthy cells (Jafri et al. 2018). Fortunately, India is a vast resource of medicinal plants and natural products. Epidemiological observation suggests that Indian herbs, spices, and their isolated phytochemicals possess significant anticancer potential and that their consumption is associated with reduction of the progression of some cancers. The anticancer properties of several phytochemicals isolated from different medicinal plants have been reported. Table 20.1 depicts the anticancer properties of some potent phytochemicals and their anticancer mechanisms.

Table 20.1 Potent phytochemicals and their anticancer mode of action against some cancers
Full size table

20.2 The Advantage of Nano-phytochemicals Over Pure Phytochemicals

Phytochemicals have potential ability to protect against many chronic diseases such as heart disease, diabetes, neuronal degeneration, and cancer (Subramanian et al. 2016). Phytochemicals possess significant antiproliferative and apoptotic effects against various cancer cells and are widely used in anticancer research (Fig. 20.1). These phytochemicals induce apoptotic effects on various cancerous cells through different apoptotic signaling pathways and check cell-cycle progression, regulating the antioxidant system and detoxification.

Fig. 20.1
figure 1

Apoptotic induction by phytochemicals and nano-phytochemicals in cancer cells

Full size image

Although the phytochemicals possess marvelous antiproliferative and apoptotic potential, they also have some limitations to be target-effective drugs because of their lower solubility in water, poor penetration power for entering targeted cells, restricted therapeutic potential, hepatic disposition, and prompt absorption by normal cells (Bhadoriya et al. 2011). Hence, to overcome these issues, scientists have shifted their interests toward a nano-based targeted drug delivery system of some promising phytochemicals to enhance their aqueous solubility, target specific to cancerous cells, improving cellular uptake, bioavailability and reducing the quantities of phytochemicals to achieve a secure therapeutic level of these potent phytochemicals for future targeted drug delivery systems (Fig. 20.2). The nano-phytochemicals also have various advantages over the pure phytochemicals in having excellent stability in the blood, a multi-efficient design, and hence improved anticancer effectiveness compared to the pure phytochemicals.

Fig. 20.2
figure 2

Schematic presentation of nanocarrier nano-phytochemicals and their advantages in cancer research

Full size image

20.2.1 Role of Nanoform Phytochemicals in Cancer Research

Nanotechnology has improved the bioavailability, solubility, and targeted delivery of active phytochemicals by using nanoparticles as a carrier and enhancing the bioactivity of potent phytochemicals (Nishiyama 2007). There are some previous reports of the active phytochemical-loaded nanoparticles targeting against cancer cells with reduced side effects. Table 20.2 shows some promising nano-phytochemicals and their anticancer potential against some cancers.

Table 20.2 Promising nano-phytochemicals and their anticancer potential against some cancers
Full size table

20.2.1.1 Broccoli Gold Nanoparticles

Broccoli (Brassica oleracea) is a cruciferous vegetable that is potentially protective against some cancers (Steinmetz and Potter 1991a, b). Broccoli phytochemicals are loaded with polyphenols, glucosinolates (GLs), vitamin C, carotene, folic acid, and fibers (Conaway et al. 2001; Mahn and Reyes 2011). These constituents enhance antioxidant activities and stimulate phase-2 detoxification enzymes (Tang et al. 2006; Qazi et al. 2010). Broccoli-loaded gold nanoparticles (B-Au NPs) were synthesized and were analyzed against some cancerous cells, such as MDA-MB-231, SkBr3, and T47D cells of breast carcinoma, PC-3 cells of prostate carcinoma, and U266 cells of myeloma to evaluate the anti-cancerous activity (Khoobchandani et al. 2013). The findings revealed that the conjugated B-Au NPs possessed excellent anti-cancerous effects against breast carcinoma, prostate carcinoma and myeloma cells.

20.2.1.2 Gold Quercetin Nanoparticles

Quercetin is a predominant flavone that possesses antioxidant and antiinflammatory properties and provides valuable health benefits to humans (Aguirre et al. 2011). It is isolated from many food items such as leafy vegetables, citrus fruits, red wine, green tea, apples, berries, onions, and Ginkgo biloba (Davis et al. 2009). A previous study reported the synthesis of gold-quercetin nanoparticles (GQ NPs) and its anticancer activity against liver carcinoma (Ren et al. 2017). The GQ NPs regulated abnormal proliferation, colony formation, and cell migration in liver cancer cells, and subsequently inhibited cancer progression. GQ NPs encouraged apoptosis in liver carcinoma cells by activation of caspases (3, 9) and expression of cytochrome c (Cyto-c). The study showed that GQ NPs impair the caspase/Cyto-c pathway, obstruct NF-κB/COX-2 and Akt/ERK1/2, and suppress AP-2β/hTERT signaling pathways.

20.2.1.3 Curcumin Nanoparticles

Curcumin has both anticancer and cancer prevention properties. Curcumin is a natural bioactive polyphenolic constituent, found in turmeric, with properties to inhibit proliferation and metastasis in a wide range of cancers (Joe et al. 2004). However, poor solubility in water has limited the systemic bioavailability of curcumin when administered orally. To overcome the solubility and bioavailability restrictions of curcumin, it was loaded on various types of nanoparticles. Methoxy polyethylene glycol (mPEG) and polycaprolactone (PCL) co-polymers enhanced the anti-cancerous activity of curcumin with efficient loading capability and sustainable release in A549 cells of lung epithelial carcinoma. This curcumin-loaded nanoparticle effectively enters into lung carcinoma A549 cells and interacts with the nucleus to encourage apoptosis (Yin et al. 2013). Poly lactic-co-glycolic acid curcumin nanoparticles (PLGA-CUR NPs) showed tumor regression properties against prostate carcinoma cells by inhibiting colony formation and cell growth in prostate cancer cell xenografted mice (Yallapu et al. 2014). PLGA-CUR NPs conjugated with epidermoid growth factor receptor were targeted to GE11 peptides in breast carcinoma cells in vitro and in a tumorous mice model. It extended the epidermal growth factor receptor (EGFR) expression in MCF-7 cells of breast carcinoma and reduced the phosphoinositide-3 kinase pathway, suppressed tumor growth, suppressed cancer cell proliferation, and improved drug clearance from the circulation (Jin et al. 2017). Curcumin-loaded magnetic nanoparticles were also significantly taken up in MDA-MB-231 cells of human epithelial breast carcinoma. These nanoparticles showed strong anticancer activity via strong penetration power into the cell by endocytosis (Yallapu et al. 2012). The uploaded curcumin magnetic nanoparticles exhibited strong magnetic resonance properties and potentially enhanced the anticancer targeting capacity of curcumin.

Nano-curcumin effectively decreased the level of miRNA-21, β-catenin, and the expression of E6/E7 HPV oncoproteins in a mouse cervical cancer model (Zaman et al. 2016). Also, curcumin-loaded silica nanoparticles (Dinda et al. 2012) and curcumin-loaded folate-modified chitosan nanoparticles (Esfandiarpour-Boroujeni et al. 2017) have significant anticancer effect against HepG2 cells of hepatocellular carcinoma and MCF-7 cells of breast carcinoma, respectively.

20.2.1.4 Selaginella doederleinii Leaf Nanoparticles

Selaginella doederleinii Hieron possesses several bioactive phytochemicals and has been extensively used in traditional herbal medicine for curing rheumatoid arthritis and various cancers, specifically lung cancer, cervical cancer, choriocarcinoma, and nasopharyngeal carcinoma (Abdille et al. 2005; Ishii et al. 2005; Wang et al. 2015). Selaginella leaf extract nanoparticles (SDNPs) reduced the viability of lung carcinoma A549 cells and were least toxic to normal Chang liver cells (Syaefudin et al. 2016). The findings revealed the apoptotic potential of SDNPs and the targeted drug delivery system without affecting the normal Chang cells.

20.2.1.5 Nigella sativa Nanoformulation

Nigella sativa , commonly known as nigella, kalonji, black caraway, and black cumin, is broadly used as a traditional medicine universally (Heiss and Oeggl 2005). Thymoquinone is one of the major active phyto-constituents present in Nigella sativa and possesses various pharmacological properties: antimicrobial, antiinflammatory, antipyretic, hypoglycemic, analgesic, and antioxidant (Ali and Blunden 2003). Previous studies reported the anticancer and antimutagenic activity of thymoquinone in Caco-2, HT-29, HCT-116, DLD-1, and LoVo cancerous cells (Gali-Muhtasib et al. 2006). The encapsulated thymoquinone (TQ) nanoparticles (TQ NPs) were synthesized with the help of biodegradable polyvinyl pyrrolidone (PVP) and polyethylene glycol (PEG) (less than 50 nm in size) and significantly enhanced anticancer efficacy by increasing bioavailability and solubility (Bhattacharya et al. 2015) of TQ. In vitro study in MCF-7 cells of breast carcinoma and in vivo tumor-bearing mice demonstrated that PEG-TQ NPs enhance miR-34a, repress Rac1 mRNA protein expression, prevent cell migration, and hinder angiogenesis. TQ loaded with modified molecular micelles, PLGA nanoparticles, and chitosan myristic acid nanogel exhibited more antioxidant and antiproliferative effectiveness at low doses with controlled release as compared with pure TQ against MCF-7 cells and MDA-MB-231 of breast carcinoma (Ganea et al. 2010; Dehghani et al. 2015). These findings showed that TQ NP have a more potent apoptotic effect than pure TQ.

20.2.1.6 Honokiol Nanoparticle

Honokiol is a polyphenol, a lignan obtained from the medicinal plant Magnolia officinalis (Li et al. 2008). It possesses multifactorial pharmacological properties and is widely used to treat stomach upset, inflammation, nervous disturbance, and anxiety (Chiang et al. 2006; Kim and Cho 2008; Deng et al. 2008; Fried and Arbiser 2009). It also showed antineoplastic and apoptotic effectiveness against various cancerous cells (Yuan et al. 2009; Steinmann et al. 2012; Avtanski et al. 2013; Cheng et al. 2014; Subramaniam et al. 2015). Honokiol-loaded synthesized nanoformulation co-polymer micelles with monomethoxy polyethylene glycol and polycaprolactone (HK-MPEG/PCL) increased bioavailability and solubility. The anticancer activity of HK-MPEG/PCL showed reduced tumor growth and apoptotic induction in a cancer nude mouse model and prevented angiogenesis (Cheng et al. 2016). Another study on honokiol-loaded co-polymer synthesized with folate and polyethyleneimine nanoparticles (HK NPs) significantly prevented metastasis, proliferation, tumor growth, angiogenesis, and cell-cycle progression (Gou et al. 2010). The developed HK NPs potentially encouraged apoptosis of HNE-1 cells of nasopharyngeal carcinoma as compared to pure honokiol.

20.2.1.7 Silibinin-Loaded Nanoparticle

Silibinin is a natural antioxidant and a polyphenolic flavonoid found in Silybum marianum, also known as silybin or milk thistle (Davis-Searles et al. 2005). It possesses multifactorial pharmacological effects such as hepato-protective, antioxidant, and anticarcinogenic activities. Silibinin encourages apoptosis via inhibiting cell-cycle progression, preventing proliferation, impairs angiogenesis, and enhancing immune stimulation in several cancers (Mateen et al. 2010; Nejati-Koshki et al. 2012; Surai 2015). Some previous studies demonstrated that silibinin arrested the cancer cycle and inhibited the growth, progression, and angiogenesis of tumorous cells (Singh et al. 2006; Liang et al. 2014). Silibinin-loaded nanoparticles with PLGA-PEG co-polymer were synthesized to evaluate the anticancer potential and expression of the hTERT gene in T47D cells of breast carcinoma and A549 cells of lung carcinoma. The findings showed that hTERT expression more efficiently reduced the cell viability of both cancerous cells with the increasing concentrations of nano-silibinin as compared to the pure silibinin (Ebrahimnezhad et al. 2013; Amirsaadat et al. 2017). The silibinin-loaded phosphatidylcholine lipid nanoparticles significantly reduced the growth and angiogenesis of breast carcinoma (Xu et al. 2013). These findings suggested that nano-form silibinin was a more efficient anticancer agent than pure silibinin.

20.2.1.8 Ursolic Acid Nanoparticle

Ursolic acid is a plant-derived triterpenoid that is present in epicuticular waxes of apples, fruit peels, herbs, and spices such as rosemary and thyme (Shanmugam et al. 2013). Ursolic acid has multifactorial pharmacological properties, such as antiinflammatory (Chattopadhyay et al. 2002), antidiabetic (Jang et al. 2010), antiepileptic, anticancer (Tannock 2011), and liver protective (Shanmugam et al. 2011; Prasad et al. 2011) elements. Ursolic acid-based mesoporous silica nanospheres (UAMSN) were synthesized with the help of pH-sensitive chitosan and folic acid for the targeted drug delivery of tumor cells (Jiang et al. 2017). Enhanced apoptotic effects of ursolic acid-encapsulated PLGA nanoparticles (UA-NPs) were found in B16F10 mouse melanoma cells as compared with pure ursolic acid (Baishya et al. 2016). Folate and chitosan-based nanocarriers for the delivery of ursolic acid (FA-CS-UA-NPs) were studied for in vitro MCF-7 cells of breast carcinoma and in an in vivo tumor xenograft mouse model (Jin et al. 2016). The findings revealed FA-CS-UA-NPs penetrated into the cells via endocytosis and encouraged apoptosis. The FA-CS-UA-NPs had the potential to localize into the mitochondria, induce excessive reactive oxygen species (ROS), and enhance apoptosis in cancerous cells.

20.2.1.9 β-Lapachone Nanoparticle

Beta-lapachone is a quinone that is abundant in the bark of Tabebuia avellanedae (Lapacho tree) and has potent anti-cancerous properties (Pardee et al. 2002). It generates apoptosis via modulating NADPH quinone oxidoreductase-1 (NQO1) in cancerous cells (Blanco et al. 2007). Lapachone-loaded silver nanoparticles (Lap Au NPs) were synthesized and targeted on anti-EGFR antibody through intravenous injection of Lap Au NPs to tumor-bearing xenografted mice, showing an enhanced tumor suppression effect as well as enhanced radiotherapeutic efficacy (Jeong et al. 2009).

20.2.1.10 Ferulic Acid Nanoparticles

Ferulic acid is a phenolic phytochemical found in vegetable sources, oat flours, whole grain wheat, and rice (Zhao and Moghadasian 2008; Kumar and Pruthi 2014). A ferulic acid-loaded synthesized PLGA nanoparticle (FA-PLGA-NP) enhances apoptosis in NCI-H460 cells of lung carcinoma as compared to its pure form (Merlin et al. 2012). The FA-PLGA-NPs encourage apoptosis via decreasing cell proliferation, generating excessive intracellular ROS, enhanced DNA damage, and lipid peroxidation.

20.3 Conclusion

Numerous studies on phytochemicals have shown significant anticancer potential but some limitations. Studies on nano-phytochemicals, both in vitro and in animal models, showed enhanced bioavailability, improved cellular uptake, reduced doses, and enhanced solubility, overcoming the limitations of pure phytochemicals. Further, the potent anticancer nano-phytochemicals without side effects that are not destructive to normal cells are still to be investigated. The ongoing research on nano-phytochemicals opens a new avenue for cancer cure by following promising phytochemicals with the advanced approaches of nanotechnology.