EssayUse of cancer chemopreventive phytochemicals as antineoplastic agents
Introduction
An abundance of mechanistic information has become available on how phytochemicals derived from dietary sources (figure 1), which have putative chemopreventive properties, interfere with tumour promotion and progression.1 Some of the mechanisms used by these agents—eg, modulation of oncogenic kinases or cell-cycle regulatory molecules—are identical to those through which molecularly targeted chemotherapeutic agents exert their activity.2 Therefore, chemopreventive phytochemicals could in theory serve as alternatives to chemically designed antineoplastic agents, as constituents of therapeutic drug combinations in advanced disease, or as adjuvant treatments. This argument makes economic sense because the costs associated with the generation or isolation and development of phytochemicals might well be lower than those associated with the discovery and development of new chemical entities. In this essay, we discuss the hypothesis that phytochemicals suspected to prevent cancer can also have a role in the treatment of neoplastic conditions and consider issues such as the mechanisms which these agents share with chemotherapeutic agents, their pharmacokinetic properties, and their potential clinical development. The polyphenols curcumin, epigallocatechin gallate, resveratrol, and indole-3-carbinol serve as examples of a wide variety of naturally occurring phytochemicals with proven or suspected chemopreventive activity (figure 2).
Section snippets
Chemotherapeutic mechanisms
Analogous to molecularly targeted chemotherapeutic drugs, chemopreventive phytochemicals confound events in host and tumour tissue that sustain the hallmarks of cancer—acquisition of self-sufficiency in growth signals, insensitivity to signals that usually inhibit proliferation, use of survival pathways to avoid the apoptosis that can occur in irreversibly damaged cells, the ability to replicate indefinitely, initiation of angiogenesis to ensure sufficient oxygen and nutrient supply to sustain
Confounding of cell growth and survival
The growth-inhibitory and apoptosis inducing properties of curcumin, resveratrol, epigallocatechin gallate, and indole-3-carbinol have been well documented. Here, we discuss a few examples of mechanisms by which these agents are thought to compromise cancer-cell survival (figure 3). These mechanisms operate in a cell-specific fashion and frequently only within a narrow concentration window.
Curcumin4 and resveratrol5 can induce apoptosis by upregulation of the proapoptotic proto-oncogenes BAX
Anti-inflammatory effects
Inflammatory stimuli, such as those triggered by the cycoloxygenase (COX) enzyme COX2, sustain carcinogenesis in tissues like the colorectum, breast, and lung. Reduction of inflammation has been discussed as a viable cancer chemotherapeutic mechanism—eg, for trabectedin.21 Curcumin and resveratrol can exert anti-inflammatory mechanisms, and their abilities to interfere with the inflammatory cascade mediated by eicosanoids, COX enzymes, and lipoxygenases and to inhibit NFκB activation have been
Chemosensitising effects
Several studies have documented the ability of chemopreventive phytochemicals to increase the sensitivity of cancer cells to conventional anticancer drugs. Indole-3-carbinol,24, 25 curcumin,26, 27, 28, 29 epigallocatechin gallate,30, 31, 32 and resveratrol33 counteract drug resistance mediated by multidrug resistance protein or multidrug resistance-related protein in various cancer cells in vitro. Information on sensitisation in animals in vivo is much less abundant, but it has been shown for
Whole-diet matrix versus isolated phytochemicals
The doses at which phytochemicals are ingested with the diet are, in general, orders of magnitude below those needed to give pharmacologically active concentrations. Therefore, diet-derived phytochemicals need to be considered from two viewpoints: first, in their role as actual dietary constituents, in which they might exert pharmacological actions at very low concentrations together with many other food ingredients with the involvement of potentially synergistic or antagonistic interactions,
Clinical pharmacology
Many chemopreventive phytochemicals are polyphenols. By their very nature, phenols are prone to undergo metabolic conjugation, and such conjugates are almost invariably devoid of pharmacological activity. Ample data on the pharmacokinetics of these polyphenols in animals suggest that they have varying degrees of restricted systemic availability, probably related, at least partly, to their avid metabolic disposition. Poor bioavailability has been shown for curcumin,37, 38, 39 resveratrol,40, 41
Phytochemicals in combination treatment
Treatment of malignant diseases with a combination of a suitable chemopreventive phytochemical and an established anticancer agent might be a realistic and promising option. Additive or synergistic actions of chemopreventive phytochemicals have been recorded (eg, epigallocatechin gallate substantially enhanced the growth-inhibitory effects of fluorouracil in head and neck squamous carcinoma cells at concentrations that have been found in serum after oral administration).45 But interactions
Phytochemical drug development
When chemopreventive phytochemicals are considered for use within a defined chemotherapeutic framework, their antineoplastic effects need to be checked in suitable animal models and ultimately in pharmacokinetic and pharmacodynamic pilot studies in human beings. The long-term experience, that we have of phytochemicals as diet constituents, suggest that they do not elicit adverse effects in human beings. Nevertheless, their safety needs utmost scrutiny, because the doses at which they are to be
Conclusions
Clinical experience with the EGFR tyrosine kinase inhibitors suggests that the molecular signature of a tumour determines its susceptibility towards the effects of molecular targeted drugs,51 suggesting that oncologists will eventually want to use a range of agents capable of interfering with neoplastic cell survival in diverse ways counteracting the corollary of the different bespoke molecular signatures driving the malignant diseases. In view of the evidence emerging from studies of the
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