Ovarian
carcinoma is the most deadly gynecological
malignancy. Current chemotherapeutic drugs are only transiently effective and patients with advance disease often develop resistance despite significant initial responses. Mounting evidence suggests that
anti-apoptotic proteins, including those of the
inhibitor of apoptosis protein (IAP) family, play important roles in the chemoresistance. There has been a recent emergence of compounds that block the IAP functions. Here, we evaluated
AT-406, a novel and orally active antagonist of multiple IAP
proteins, in
ovarian cancer cells as a single agent and in the combination with
carboplatin for therapeutic efficacy and mechanism of action. We demonstrate that
AT-406 has significant single agent activity in 60% of human
ovarian cancer cell lines examined in vitro and inhibits
ovarian cancer progression in vivo and that 3 out of 5
carboplatin-resistant cell lines are sensitive to
AT-406, highlighting the therapeutic potential of
AT-406 for patients with inherent or acquired
platinum resistance. Additionally, our in vivo studies show that
AT-406 enhances the
carboplatin-induced
ovarian cancer cell death and increases survival of the experimental mice, suggesting that
AT-406 sensitizes the response of these cells to
carboplatin. Mechanistically, we demonstrate that
AT-406 induced apoptosis is correlated with its ability to down-regulate XIAP whereas
AT-406 induces cIAP1 degradation in both
AT-406 sensitive and resistance cell lines. Together, these results demonstrate, for the first time, the anti-
ovarian cancer efficacy of
AT-406 as a single agent and in the combination with
carboplatin, suggesting that
AT-406 has potential as a novel
therapy for
ovarian cancer patients, especially for patients exhibiting resistance to the
platinum-based
therapies.