Genistein: A novel inhibitor of IL-6/IL-6R interface of the Interleukin-6-mediated STAT3 dependent pathway of carcinogenesis

Phytotherapy for breast cancer, the second most common cancer diagnosed among women and a leading cause of their death globally, may serve as an adjuvant therapy to combat adverse chemo-and radiotherapy challenges. IL-6/STAT3 signaling pathway, governing breast cancer progression, remains a favourite therapeutic target in developing phytotherapy. Therefore, identifying phytocompounds with novel targets influencing the IL-6/STAT3 pathway would help to develop phytotherapy for breast cancer. In this study, we demonstrate the novel binding site, i.e., the interface of IL-6 and IL-6R alpha of the IL-6/STAT3 signaling pathway of cancer progression. Ten potent anticancer phytocompounds were analyzed for their binding with IL-6/IL-6R alpha complex using molecular docking and molecular dynamics simulations. Among all, genistein showed excellent binding energy (-10.59 kcal/mol) with the IL-6/IL-6R alpha interface of the STAT3 pathway. In cytotoxicity experiment, Genistein showed IC50 of 38 mu M and 18 mu M for 24 and 48 h, respectively, whereas quercetin showed IC50 of more than 50 mu M and 35 mu M at 24 h and 48 h, respectively on MDA-MB-453 breast cancer cell line. Based on bioinformatic analyses and cellular toxicity assay, we propose genistein as a potential therapeutic phytocompound to inhibit the IL-6/STAT3 pathway by blocking the interaction of IL-6 with the IL-6 receptor.(c) 2022 Elsevier B.V. All rights reserved.

Automated summary

Phytotherapy for breast cancer, as an adjuvant therapy, has shown potential in overcoming the challenges of chemotherapy and radiotherapy. In this study, the researchers identified genistein as a phytocompound with excellent binding energy to the IL-6/IL-6R alpha interface of the STAT3 pathway. They propose genistein as a potential therapeutic compound to inhibit the IL-6/STAT3 pathway in breast cancer.