The cyclin-dependent kinase inhibitor AT7519 augments cisplatin's efficacy in ovarian cancer via multiple oncogenic signaling pathways.

Abstract

Although cisplatin is the most active drug for the treatment of ovarian cancer, majority of patients develop resistance and ultimately relapse. Enhancing the efficacy of cisplatin could represent a promising strategy to improve the clinical outcome of patients with ovarian cancer. AT7519 is a multitargeted cyclin-dependent kinase (CDK) inhibitor and displays potent anticancer activities. In this work, we show that the combination of AT7519 with cisplatin is much more superior to cisplatin alone in inhibiting ovarian cancer. AT7519 at nanomolar concentrations inhibits proliferation and migration and induces apoptosis of multiple ovarian cancer cell lines. In contrast, AT7519 at the same concentrations either does not affect survival or is significantly less effective in inhibiting proliferation and migration in normal ovarian cells and fibroblast cells. AT7519 significantly augments the inhibitory effects of cisplatin in ovarian cancer cells in a dose-dependent manner. Mechanistic studies suggest that AT7519 (i) inhibits proliferation via decreasing activities of CDK1 and 2, and via inhibiting RNA transcription; (ii) inhibits migration via suppressing epithelial-mesenchymal transition (EMT); and (iii) induces apoptosis via decreasing Mcl-1 and increasing Bim in ovarian cancer cells. Using a human ovarian cancer xenograft mouse model, we confirm the in vivo efficacy of AT7519 alone, and the synergistic effects of AT7519 and cisplatin in combination, at doses that cause minimal toxicity in mice. Our findings provide systematic preclinical evidence to support the initialization of clinical trials of the AT7519 and cisplatin combination for the treatment of ovarian cancer.