An overview on the role of dietary phenolics for the treatment of cancers - PubMed (original) (raw)

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An overview on the role of dietary phenolics for the treatment of cancers

Preethi G Anantharaju et al. Nutr J. 2016.

Abstract

Plant derived phenolic compounds have been shown to inhibit the initiation and progression of cancers by modulating genes regulating key processes such as: (a) oncogenic transformation of normal cells; (b) growth and development of tumors; and (c) angiogenesis and metastasis. Recent studies focusing on identifying the molecular basis of plant phenolics-induced cancer cell death have demonstrated down-regulation of: (a) oncogenic survival kinases such as PI3K and Akt; (b) cell proliferation regulators that include Erk1/2, D-type Cyclins, and Cyclin Dependent Kinases (CDKs); (c) transcription factors such as NF-kβ, NRF2 and STATs; (d) histone deacetylases HDAC1 and HDAC2; and (e) angiogenic factors VEGF, FGFR1 and MIC-1. Furthermore, while inhibiting oncogenic proteins, the phenolic compounds elevate the expression of tumor suppressor proteins p53, PTEN, p21, and p27. In addition, plant phenolic compounds and the herbal extracts rich in phenolic compounds modulate the levels of reactive oxygen species (ROS) in cells thereby regulate cell proliferation, survival and apoptosis. Furthermore, recent studies have demonstrated that phenolic compounds undergo transformation in gut microbiota thereby acquire additional properties that promote their biological activities. In vitro observations, preclinical and epidemiological studies have shown the involvement of plant phenolic acids in retarding the cancer growth. However, to date, there is no clinical trial as such testing the role of plant phenolic compounds for inhibiting tumor growth in humans. More over, several variations in response to phenolic acid rich diets-mediated treatment among individuals have also been reported, raising concerns about whether phenolic acids could be used for treating cancers. Therefore, we have made an attempt to (a) address the key structural features of phenolic acids required for exhibiting potent anti-cancer activity; (b) review the reported findings about the mechanisms of action of phenolic compounds and their transformation by gut microbiota; and

Keywords: Anti-cancer activity; Benzoic acid; Caffeic acid; Cinnamic acid; Gallic acid; Phenolic compounds; Tumor growth.

(c) update the toxicological aspects and anti-tumor properties of phenolic compounds and extracts containing phenolic compounds in animals.

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Figures

Fig. 1

Fig. 1

Synthesis of plant phenolic compounds by shikimate pathway, shows the biosynthetic pathway of plant phenolic acids [135]. The phosphoenolpyruvate react with erythrose-4-phosphate to give chorismic acid, which is a precursor for tyrosine and phenylalanine which later serves as precursors for cinnamic acid derivatives. Predominantly benzoic acids are synthesized from chorismic acid via oxidative and non-oxidative pathways while iso chorismic acid serve as precursor for protocatechuic acid [136]

Fig. 2

Fig. 2

Classifications of the plant phenols, based on their structure. Broadly plant phenolic compounds are classified as simple and complex phenolic acids. Simple phenolic acids are further classified as benzoic and cinnamic acid derivatives while complex phenolic acids are classified as flavonoids, tannins and stilbenes

Fig. 3

Fig. 3

Gut microbiota mediates the transformation of phenolic compounds and enhance the health beneficial effects. Bound and complex phenolic compounds undergo bio-transformation in the human gastro intestinal tract by the gut microbiota into simple and easily bioavailable phenolic compounds. The active metabolites produced by the biotransformation have proven to exhibit better pharmacological actions and possess better health beneficial properties compared to corresponding untransformed compounds

Fig. 4

Fig. 4

Key structural motifs responsible for anticancer activity Studies on the structure-activity-relationship (SAR) of phenolic compounds have identified the aromatic ring (represented with an arrow), number and position of free hydroxyl groups (represented with a circle) and unsaturated fatty acid chain as key structural motifs required for exhibiting anticancer activity (represented with square)

Fig. 5

Fig. 5

Key processes effected by plant phenolic acids Phenolic compounds are known to modulate the expression of key proteins such as BCL2, BAX, AKT, STAT. While suppressing the oncogenic proteins, phenolic compounds induce the expression of tumor suppressors P53, P21 and P27. As a result, phenolic compounds trigger apoptotic cell death while inhibiting the proliferation and inducing the cell cycle arrest [47]

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