Polyphenolic molecules targeting signal transducer and activator of transcription 3 pathway for the treatment of cancer

Abstract Cancer is accounted as the second-highest cause of morbidity and mortality throughout the world. Numerous preclinical and clinical investigations have consistently highlighted the role of natural polyphenolic compounds against various cancers. A plethora of potential bioactive polyphenolic molecules, primarily flavonoids, phenolic acids, lignans and stilbenes, have been explored from the natural sources for their chemopreventive and chemoprotective activities. Moreover, combinations of these polyphenols with current chemotherapeutic agents have also demonstrated their strong role against both progression and resistance of malignancies. Signal transducer and activator of transcription 3 (STAT3) is a ubiquitously-expressed signaling molecule in almost all body cells. Thousands of literatures have revealed that STAT3 plays significant roles in promoting the cellular proliferation, differentiation, cell cycle progression, metastasis, angiogenesis and immunosuppression as well as chemoresistance through the regulation of its downstream target genes such as Bcl-2, Bcl-xL, cyclin D1, c-Myc and survivin. For its key role in cancer development, researchers considered STAT3 as a major target for cancer therapy that mainly focuses on abrogating the expression (activation or phosphorylation) of STAT3 in tumor cells both directly and indirectly. Polyphenolic molecules have explicated their protective actions in malignant cells via targeting STAT3 both in vitro and in vivo. In this article, we reviewed how polyphenolic compounds as well as their combinations with other chemotherapeutic drugs inhibit cancer cells by targeting STAT3 signaling pathway.