Discovery of rafoxanide as a dual CDK4/6 inhibitor for the treatment of skin cancer.

Discovery of rafoxanide as a dual CDK4/6 inhibitor for the treatment of skin cancer. Oncol Rep. 2018 Jun 27;: Authors: Shi X, Li H, Shi A, Yao H, Ke K, Dong C, Zhu Y, Qin Y, Ding Y, He YH, Liu X, Li L, Lei L, Hai Q, Chen W, Leung KS, Wong MH, Kung HF, Lin MC Abstract Since cyclin‑dependent kinases 4/6 (CDK4/6) play pivotal roles in cell cycle regulation and are overexpressed in human skin cancers, CDK4/6 inhibitors are potentially effective drugs for skin cancer. In the present study, we present a mixed computational and experimental study attempting to repurpose approved small‑molecule drugs as dual CDK4/6 inhibitors for skin cancer treatment. We performed structure‑based virtual screening using the docking software idock, targeting an ensemble of CDK4/6 structures. We identified and selected nine compounds with significant predicted scores, and evaluated their cytotoxic effects in vitro in A375 and A431 human skin cancer cell lines. Rafoxanide was found to exhibit the highest cytotoxic effects (IC50: 1.09 µM for A375 and 1.31 µM for A431 cells). Consistent with the expected properties of CDK4/6 inhibitors, rafoxanide significantly increased the G1 phase population. Notably, we revealed that rafoxanide specifically decreased the expression of CDK4/6, cyclin D, retinoblastoma protein (Rb) and the phosphorylation of CDK4/6 and Rb. Furthermore, the anticancer effect of rafoxanide was demonstrated in vivo in BALB/C nude m...
Source: Oncology Reports - Category: Cancer & Oncology Tags: Oncol Rep Source Type: research