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.