Evidence for Multilevel Chemopreventive Activities of Natural Phenols from Functional Genomic Studies of Curcumin, Resveratrol, Genistein, Quercetin, and Luteolin

Abstract

Herein, I present an updated and contextualized literature review of functional genomic studies of natural phenols in the context of cancer. I suggest multilevel chemopreventive and anticancer mechanisms of action, which are shared by multiple dietary natural phenols. Specifically, I cite evidence that curcumin and resveratrol have multilevel anti-cancer effects through: (1) inducing either p53-dependent or p53-independent apoptosis in cancer cell lines, (2) acting as potent regulators of expression of oncogenic and anti-oncogenic microRNAs, and (3) inducing complex epigenetic changes that can switch off oncogenes/switch on anti-oncogenes. There is no simple reductionist explanation for anti-cancer effects of curcumin and resveratrol. More generally, multilevel models of chemoprevention are suggested for related natural phenols and flavonoids such as genistein, quercetin, or luteolin.

Keywords: cancer; chemoprevention; curcumin; genistein; genomics; luteolin; quercetin; resveratrol.

Figure 1

Chemical structures of curcumin, resveratrol, genistein, quercetin, and luteolin. This figure shows chemical structures (top row), space-filling models (medium row), and exact mass (bottom row) of curcumin, resveratrol, genistein, quercetin, and luteolin. Curcumin is a diarylheptanoid from the group of curcuminoids, while resveratrol is a 3,4′,5-trihydroxy-trans-stilbene. Genistein, quercetin, and luteolin are flavonoids derived from a 15-carbon skeleton with two aromatic phenyl rings (A and B). Flavonoids also contain a heterocyclic pyran ring (C) with an embedded oxygen. These are small molecules—with molecular weight between 228 and 368—that are aromatic. For example, curcumin and resveratrol contain two aromatic phenyl rings. Note that such natural phenols are chemically active in many types of organic reactions that are common in a living cell, such as free radical chemistry, nucleophilic addition, or metal ion interactions [8].

Figure 2

Natural phenols induce complex gene expression changes that can be studied using functional genomics and anti-reductionist bioinformatics.

Figure 3

A circuit board for initiation, amplification, and execution of apoptosis. Apoptosis is initiated through either a p53-dependent (intrinsic) or independent (extrinsic) pathway. The intrinsic apoptosis pathway is p53-dependent [34] and is initiated by pathological internal cellular states such as DNA damage or aberrant metabolism. Cyclin-dependent kinase inhibitor 1—p21 [35] and cyclin-dependent kinase inhibitor—p27 [36] are key inhibitors of the cell cycle that is transcriptionally induced by p53. Interestingly, mutated p53 is frequently stabilized by mutations rather than depleted in cancer cells [37]. This is because normal p53 functions within a dynamic cycle of production and degradation known as the futile cycle. Indeed, mutated p53 forms lack normal transcriptional activity and fail to transcriptionally induce MDM2—a protein that induces rapid p53 ubiquitination [38].