Translational Phytomedicines against Cancer: Promise and Hurdles

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regular intake of fruits and vegetables. 4 In 2002, WHO reported around 2.7 million deaths/year worldwide due to low intake of fruits and vegetables. More than 1000 chemo preventive phytochemicals have been identified in various preclinical studies. It was estimated that more than 100 important phytochemicals can be obtained from just one vegetable serving. 5 The importance of vegetables and fruits in chemoprevention and the increasing number of cancer cases geared implementation of several international chemo preventive initiatives such as A Five-A-Day for better health program, Savor the spectrum, European prospective investigation of cancer and nutrition, Global strategy on dietary prevention of cancer, etc. 6 Phytochemicals are an integral candidate in the prevention of cancer as they can be taken through a daily diet rich in fruits and vegetables or a supplement that can provide active phytochemical in the required daily dose. But this strategy will only work after proper validation of phytochemical in terms of efficacy, safety through well-designed clinical studies to achieve the desired protection against various cancer.
Dietary phytochemicals elicit chemo preventive effects either by blocking carcinogenesis or suppressing the transformation of pre-neoplastic cells to neoplastic cells. Cancer blocking agents prevent metabolic activation of pro-carcinogens and boost up their detoxification, thereby inhibiting the initiation of carcinogenesis. Most of the compounds showed a significant effect in various preclinical studies. Sulforaphane, ellagic acid, and indole-3-carbinole are the important phytochemicals with cancer blocking action, whereas beta carotene, curcumin, EGCG, resveratrol, 6-gingerol, genistein, capsaicin, etc are reported to have cancer-suppressing action by induction of apoptosis and differentiation, inhibition of oncogene activity as well as scavenging free radical, etc. 7 Several epidemiological studies suggested the cancer-preventing effect by regular intake of flavonoid rich food as well Phyto molecules mainly curcumin, quercetin (NCT01538316, NCT03476330), berberine (NCT03281096), sulforaphane (NCT03232138), EGCG (NCT02891538, NCT00917735), resveratrol (NCT00098969, NCT00578396), kaempferol, silibinin, luteolin, baicalein, etc via inhibition of pro-carcinogenic signaling that triggers the malignant transformation of cells. 8 But, upon evaluating in an in vivo or clinical setting, majority of the mainstream phytochemicals failed to achieve an effective in vivo effect, which is apparently due to the associated PK issues. However, structural or nano analogs of phytochemicals are being extensively developed and evaluated for chemo preventive action.
Many research studies revealed the potential of a large number of phytochemicals mainly flavonoids, polyphenols, alkaloids, terpenoids, carotenoids, saponins, and quinones to enhance the sensitivity of cytotoxic drugs against the cancer cells. This may promote a change from the conventional one drugone target concept to combination therapies with safeeffective phytochemicals. 9 Evidence of plant-based chemoprevention leads to more research findings of the molecular target of phytochemical to exert inhibitory effects on the cancer cell. These studies revealed the chemo sensitizing potential of phytochemical due to its ability to target relevant pathways involved in drug resistance with no or least toxicities. The emergence of multidrug resistance is posing a major obstacle in establishing an effective systemic drug therapy against cancer. Therefore, among the different strategies put forward to enhance the efficacy of conventional chemotherapeutics, phytochemical chemosensitizers are getting much acceptance nowadays because of their effectiveness and excellent safety. A detailed investigation of published literature found that phenolic phytochemicals such as curcumin, genistein, EGCG, quercetin, emodin, resveratrol are mostly reported with remarkable chemo sensitizing potential than other phytochemical classes.
Most of the phytochemicals can simultaneously modulate multiple targets involved in chemoresistance. Diverse signaling events and multiple regulators of drug transport, apoptosis, cell survival, DNA repair, epithelial-mesenchymal transition are involved in the emergence of chemoresistance. The most figured out factor involved in drug resistance is the overexpression of efflux pumps (MDR1, p-gp, LRP, BCRP) which trigger the pumping out of drugs, thus unable to maintain cytotoxic concentration within the cell. Similarly, escape from cell death mechanism mainly apoptosis is another factor conferring resistance which is characterized by decreased levels of pro-apoptotic regulators such as p-53, Apaf-1, Bax and overexpression of anti-apoptotic factors such as Bcl-2, Bcl-xl, Mcl-1. Hypoxia, oxidative stress and inflammation can also contribute to MDR by overexpression of ROS, HIF-1 and NK-κB. 10 These multi-targets of MDR rationally reveal the logic for phytochemical chemosensitization rather than available synthetic sensitizers such as verapamil or dexverapamil which act via modulating any one of the signaling events in MDR and thus, seems inadequate and ineffective.
Curcumin enhances the cytotoxic potential of paclitaxel, docetaxel, gemcitabine, 5-FU, vinblastine, vincristine, and cisplatin by modulating multitude signaling such as NK-κB, Bcl2, Bax, Bak, surviving, VEGF, EGFR, IGF, MMP-9, P-gp etc. [11][12][13] Furthermore, quercetin sensitizes doxorubicin, TRAIL, cisplatin, temozolomide by targeting resistance-conferring molecules such as HIF-α, surviving, MRP, p53, Akt, ERK, PKC. 14,15 Our research team also reported the potential of kaempferol to sensitize sorafenib against resistant hepatocellular carcinoma cells. Molecular, as well as docking studies, confirmed that kaempferol work on resistant cancer cells by inhibiting mTOR, TGF-beta and P-gp and our team proposed that kaempferol can be validated as a potent yet safe mTOR inhibitor. 16,17 As of 2013, approximately, there are more than six hundred published in vitro studies and around two hundred in vivo reports on the chemo sensitizing potential of phenolic compounds, which is significantly more than its reports for chemo preventive and chemotherapeutic effect. 18 Most of the phytochemicals that showed promising chemo sensitizing potential in preclinical evaluation have undergone clinical studies. Phytochemicals such as curcumin (NCT00295035, NCT00192842), green tea polyphenone E (NCT01116336, NCT00707252, NCT00088946), and genistein (NCT00376948, NCT00244933) were evaluated in clinical trial in combination with Erlotinib and gemcitabine against various cancers. Unfortunately, the molecules did not achieve the expected clinical effect. Curcumin itself can be the predominant example as it is the extensively evaluated phytochemical for chemo sensitizing potential with remarkable outcomes in most of the preclinical evaluations. But curcumin could not achieve the expected endpoint in most of the clinical trials, which point out the pharmacokinetic issues that make it unavailable in the systemic circulation. Likewise, resveratrol is also withdrawn from a clinical study, as it reported the development of cast nephropathy in 1/5 th of patients. 19 Regardless of the immense chemo sensitizing property, the pharmacokinetic issues such as poor water solubility, rapid metabolism, short half-life and lack of toxicity studies hinder the clinical utility of phytochemicals. Several strategies are being evaluated to overcome the challenges with the application of nanotechnology. Resveratrol, curcumin, epigallocatechin, quercetin, rutin, betulinic aid, artemisinin, ginseng are the mainstream phytochemicals being converted to bioavailable nanoformulations such as a nanoparticle, liposome, phytosome, nano emulsion etc. But, still needs to be validated in well-designed clinical trials in terms of efficacy as well as safety.
Plant based chemotherapeutics are the extensively investigated category of phytoresearch as 80 % of people worldwide rely on nature for primary health care and about 60% of currently used anticancer drugs are directly or indirectly derived from nature. Specifically, among the 240 chemotherapeutic agents approved in the last 40 years, 191 are derived from nature and the remaining 49 include the synthetic compounds derivatized from plant-based pharmacophore. 20 A commonly available, as well as affordable phytochemical which can target major signaling molecules of cancer promotion, metastasis, and resistance with no toxic side effect, will be ideal for chemotherapy. Phytochemicals approved as chemotherapeutic agents can be majorly categorized as vinca alkaloids, epipodophyllotoxin, taxanes, and camptothecin derivatives. 21 Vinca alkaloids and taxanes target tubulin and inhibit microtubule polymerization and thus leading to cell death. Podophyllotoxins target topoisomerase II to inhibit DNA synthesis of cancer cells whereas camptothecins target topoisomerase I to induce double-stranded breaks in DNA. Other phytochemicalderived anticancer agents are combretastatin A4, homoharringtonine, ingenol mebutate. Recently, FDA granted an orphan drug designation to uttroside B, a saponin from Solanum nigrum Linnfor the treatment of hepatocellular carcinoma and the compound showed 10 times more activity than the standard drug, sorafenib. [22][23][24] Likewise, the phytochemicals such as curcumin (NCT03980509), resveratrol(NCT00256334, NCT01476592, NCT00433576, NCT01317953), artemisinin (NCT00764036, NCT03093129, NCT04098744) and ginseng (NCT00631852, NCT02603016) are under clinical investigation against various cancer types.
Despite these tremendous research inputs, translational prominence of phytochemicals in oncology is considerably less as it warrants substantial evidence of better efficacy and least toxicity derived from welldesigned clinical studies. Vinblastine is discovered in 1950 and got FDA approval after 15 years in 1965 for the treatment of leukemia and lymphoma. Similarly, for paclitaxel, it took around 25 years for approval as the drug for the treatment of ovarian cancer after its discovery in 1970. In addition to drug lag and associated expenses, the clinical translation of phytochemicals are also hindered due to complex extraction-synthesis procedure, difficulty in characterization and optimization, pharmacokinetic issues such as poor water solubility and bioavailability, rapid metabolism, formulation issues such as instability and route of administration. [25][26][27] Most phyto-research is undergoing a track change from direct phytochemical studies to synthetic or nano analogs to cover up the translational bridge. This could be the explanation for the fact that from 2010 to 2019, approximately 10 synthetic small molecules derived from a phytochemical pharmacophore are approved against cancer. 28 Few examples are; the clinical limitations of paclitaxel especially poor bioavailability, drug-related toxicities and development of MDR is controlled to an extent with approved chemical or nano analogues such as; cabazitaxel for metastatic prostate cancer, paclitaxel poliglumex for glioblastoma multiforme, Abraxane (nanoparticle formulation of paclitaxel with improved bioavailability for refractory breast cancer and pancreatic cancer, EndoTAG-1 (Paclitaxel encapsulated in cationic lipid complex) for pancreatic cancer, as in the case of camptothecins, approved lipophilic analogues are cositecan, silatecan, gimetecan and diflomotecan and IMMUU-132, which is an antibody-drug conjugate of SN-38 (7-ethyl-10-hydroxycamptothecin) with orphan drug designation for the treatment of small cell lung cancer and pancreatic cancer. 29 Phytochemical are bestowed with enormous potential to act as chemo preventive, chemo sensitizing and chemotherapeutic agents by targeting a multitude of signaling involved in cancer initiation, promotion, progression as well as anticancer drug resistance ( Figure 1). The multitargeting ability with excellent safety and obviously, affordability and availability make phytochemicals mainstream candidates of anticancer drug discovery. With advanced technology, phytochemicals are also undergoing 'makeover' to nano-phytomedicine or synthetic analogs without any conventional demerit of phytochemicals. Though the literature is expanding day by day, the clinically proven examples of plant-based anticancer agents are still a few as they have to prove having high efficacy in well-designed clinical trials rather than preclinical studies (Table 1). Therefore, the scientific community must focus to develop phytochemicals as safe-effective-available-affordable phytomedicine or supplements to fight against cancer.