Expert Commentary: Dietary Factors and Natural Product Derivatives in Cancer Therapy

Summary

Several natural dietary factors possess potent anticancer activity. Since cancer remains a leading cause of death in the USA, these factors have been a subject of intense investigational interest for many years. They are generally nontoxic, inexpensive, and pleiotropic. However, they are also less bioavailable. Current research involving natural dietary anticancer compounds and their derivatives strives to strike a balance between their beneficial properties and the shortcomings, and this remains the focus of this commentary.

Introduction

Natural products have traditionally played a significant role in the drug discovery process [1]. This is particularly true for anticancer drugs, for which it is estimated that over a period of approximately 74 years (from the 1940s to 2014), 49% of all US Food and Drug Administration (FDA)‐approved drugs were either direct natural products or their derivatives [1]. This clearly underlines the importance of natural products in our fight against cancer. These natural anticancer agents afford multiple advantages, the foremost being that many natural agents are part of the normal human diet and are therefore well tolerated. This brings us to an important point of recognition that a number of anticancer agents that are part of the human diet, and hence termed “dietary factors,” have a natural origin (i.e. they are found in fruits, vegetables, spices, etc.). However, it is important to recognize that many natural anticancer compounds are not part of normal human diets; rather, they are just found in nature. Such nondietary anticancer compounds also fit into the class of “natural” anticancer agents [2, 3]. For the purpose of discussion here, we will limit ourselves to just those anticancer compounds that are natural as well as part of the human diet (i.e. dietary anticancer compounds).

Screening for Novel Anticancer Drugs of Natural Origin

Nature happens to be an excellent source of drugs, including those helping us fight cancer [4, 5]. Therefore, there has been a visible interest in screening the enormous number of natural compounds and chemical structures with putative anticancer activity. A number of approaches for the screening of natural anticancer compounds are available; these include in silico modeling [4], mathematical modeling [6], and so on. Such screening has resulted in testing of several natural agents in clinical trials [2]. However, despite all the screening and the often encouraging preclinical data, a majority of anticancer drugs fail in clinical trials [7, 8]. On an optimistic note, though, it is recognized that only a small fraction of natural resources (mostly plants) has been explored for bioactive compounds that can serve as anticancer agents [9], and thus there is scope for so much more to be done.

Dietary Anticancer Drugs: Promises and Challenges

As mentioned, dietary anticancer compounds are well tolerated, as supported by evidence from clinical trials involving several dietary anticancer compounds that were documented to be well tolerated at the doses administered [9]. This is critical, given the known toxicity associated with most anticancer regimens that do not have a natural origin [10]. While the nontoxic nature of dietary anticancer compounds is desirable, it comes at its own price. These compounds have lower bioavailability [11]. They are usually cleared by the body very efficiently, and this is often blamed for the poor outcomes in clinical trials [12].

A number of strategies have been proposed to overcome the issue of bioavailability associated with natural anticancer compounds, with primary focus on novel formulations to sustain systemic circulation and decrease turnover [13–16]. Synthesis of chemical derivatives or analogs is one such strategy that has been shown to significantly improve the bioavailability of natural anticancer compounds [17–19]. Interestingly, of the natural compounds used as anticancer drugs, it is estimated that half of them are direct natural compounds while the rest are their derivatives [9]. Clearly, the derivatives of natural anticancer compounds have their own unique place in cancer therapy. They not only improve the bioavailability but also are often reported to be significantly more active than their parent compounds [17, 19].

Another unique feature of natural compounds and their derivatives as anticancer agents is their ability to act on multiple targets (i.e. their “pleiotropic” nature) [15]. Molecularly targeted therapies that act against uniquely defined oncotargets are effective initially as they inhibit their molecular target, often leading to tumor remission. However, in a majority of cancer patients, tumor cells shift their dependency from the targeted molecule to an alternate signaling molecule or pathway [20]. In the face of adverse conditions, cancer cells reprogram their metabolism [21]. All this results in activation of parallel and/or alternative pathways of survival and proliferation, thus rendering the targeted therapy ineffective. In such a scenario, pleiotropic natural compounds can still be effective anticancer drugs by virtue of their simultaneous targeting of multiple, and often several, major oncogenic pathways.

The past several years have witnessed a shift toward personalized or precision medicine because of the realization that tumors, and probably cancer patients, are extremely heterogeneous [22, 23]. This calls for molecular characterization of cancer patients to develop tailored therapies that individual patients are most likely to benefit from. Interestingly, a role of natural anticancer compounds in such personalized cancer therapy has been advocated [24, 25]. In modern‐day cancer research, cancer stem cells, noncoding RNAs, and epigenetic alterations are being investigated as novel targets for therapy. Natural products, which were initially investigated as anticancer drugs because of their antioxidant and anti‐inflammatory properties and their ability to modulate cellular signaling, have evolved with time to now being investigated as agents that can inhibit cancer stem cells [15, 17, 26] and modulate noncoding RNAs as well as epigenetic events [15, 27].

Conclusions

Anticancer drugs of natural origin have been a focus of numerous investigations for several decades. Despite setbacks, such as low bioavailability and disappointing outcomes in several clinical trials, the interest in them has never faded. They keep coming back as modulators of key physiological phenomena that emerge as hot topics in cancer research. The pleiotropic ability of natural anticancer drugs to simultaneously affect multiple molecules and pathways is one key reason for their success. Additionally, derivatives and analogs of natural compounds have shown promise in their collective ability to fight cancer. Even though a great deal of information has been made available, our knowledge of precise mechanistic insights into the detailed anticancer activity of natural agents remains far from complete. It is important that the success witnessed in preclinical studies is translated to benefit scores of cancer patients.

References

1. 1 Newman, D.J. and Cragg, G.M. (2016). Natural products as sources of new drugs from 1981 to 2014. J. Nat. Prod. 79: 629–661.
2. 2 Cragg, G.M. and Pezzuto, J.M. (2016). Natural products as a vital source for the discovery of cancer chemotherapeutic and chemopreventive agents. Med. Princ. Pract. 25 (Suppl. 2): 41–59.
3. 3 Ruiz‐Torres, V., Encinar, J.A., Herranz‐Lopez, M. et al. (2017). An updated review on marine anticancer compounds: the use of virtual screening for the discovery of small‐molecule cancer drugs. Molecules (Basel, Switzerland) 22: 1037.
4. 4 Rayan, A., Raiyn, J., and Falah, M. (2017). Nature is the best source of anticancer drugs: indexing natural products for their anticancer bioactivity. PLoS One 12: e0187925.
5. 5 Frank, A., Abu‐Lafi, A., Adawi, A. et al. (2017). From medicinal plant extracts to defined chemical compounds targeting the histamine H4 receptor: Curcuma longa in the treatment of inflammation. Inflamm. Res. 66: 923–929.
6. 6 Carrara, L., Lavezzi, S.M., Borella, E. et al. (2017). Current mathematical models for cancer drug discovery. Expert Opin. Drug Discovery 12: 785–799.
7. 7 Kumar, S., Bajaj, S., and Bodla, R.B. (2016). Preclinical screening methods in cancer. Indian J. Pharm. 48: 481–486.
8. 8 Liu, Z., Delavan, B., Roberts, R., and Tong, W. (2017). Lessons learned from two decades of anticancer drugs. Trends Pharmacol. Sci. 38: 852–872.
9. 9 Juarez, P. (2014). Plant‐derived anticancer agents: a promising treatment for bone metastasis. Bonekey Rep. 3: 599.
10. 10 Damjanov, N. (2000). Anticancer drug toxicity: prevention, management, and clinical pharmacokinetics. Mod. Pathol. 13: 953.
11. 11 Shilpa, S., Mansi, G., Ashish, S., and Agarwal, S.M. (2018). Oral bioavailability of naturally occurring anticancer phytomolecules. Lett. Drug Des. Discovery 15: 1–1.
12. 12 Panda, A.K., Chakraborty, D., Sarkar, I. et al....