Investigation of the BH3-mimetics navitoclax and obatoclax as potential therapeutics for ovarian cancer

Abstract

Ovarian cancer is treated in most cases with a combination of surgery and chemotherapy.
However, despite the overall improvement in survival rates, over the last 30 years there has not been a break-through therapeutic development. Following first-line treatment, the majority of patients experience periods of relapse characterised by resistance to anticancer drugs. Factors which contribute to ovarian cancer chemoresistance have been identified as potential targets for drug discovery, such as the Bcl-2 family of proteins,
which regulates apoptosis. The strategy of targeting the anti-apoptotic members of the Bcl-2 family that are overexpressed in ovarian cancer has led to the discovery of BH3-mimetics. ABT-737, a selective BH3-mimetic, has been found to be synergistic with chemotherapy in ovarian cancer. In this study the activity of navitoclax, an orally available analogue of ABT-737 and obatoclax, a pan-Bcl-2 inhibitor, were evaluated in a series of
ovarian cancer models. Navitoclax demonstrated synergy with both carboplatin and paclitaxel. Obatoclax potently inhibited the growth of ovarian cancer cell cultures. In part this was due to the anticipated induction of apoptosis, but in other cell lines an additional mechanism of cell death was implicated. Surprisingly, obatoclax was neither synergistic with carboplatin nor paclitaxel. These observations may be used to inform the design of clinical trials of these agents in ovarian cancer.