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

A series of 11 compounds of phenyl–imidazole–pyrrole and 9 compounds of phenanthryl–imidazole–pyrrole were synthesized and evaluated against breast cancer cell lines differing in the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER)-2, viz., BT-474 (ER+, PR+, and HER2+), T-47D and MCF-7 (ER+, PR+, and HER2−), and MDA-MB-468 and MDA-MB-231 (ER−, PR−, and HER2−). The analysis of the results indicated that the most active compounds were 5d and 5k from the phenyl–imidazole–pyrrole series and 6b and 6i from the phenanthryl–imidazole–pyrrole series (IC₅₀ < 50 µM). Molecular docking (MD) and molecular dynamics simulation (MDS) studies demonstrated that the active compounds exhibited high binding affinity to the 7NH5 (a co-crystal structure of Akt1 and its specific inhibitor) protein, which is overexpressed in many breast cancer types. The active compounds 6b and 6i reduced the viability of MDA-MB-231 and MCF-7 cells by inducing cell death mechanisms. Both compounds halted the proliferation by arresting cells in the G0/G1 phase of the cell cycle. The results are similar to those of traditional Cisplatin. Intraperitoneal administration of 6i retarded the development of EAC tumors and increased the survival of mice compared with tumor-bearing control and 5-fluorouracil (5FU)-treated positive control mice.