AT-406, an orally active antagonist of multiple inhibitor of apoptosis proteins, inhibits progression of human ovarian cancer
AT-406, an orally active antagonist of multiple inhibitor of apoptosis proteins, inhibits progression of human ovarian cancer
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DOI：
10.4161/cbt.20563
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发表时间：
2012-07-01
影响因子：
3.6
通讯作者：
Yu, Qin
中科院分区：
文献类型：
--
作者：
Brunckhorst, Melissa K.;Lerner, Dimitry;Yu, Qin
卵巢癌是最致命的妇科恶性肿瘤。目前的化疗药物仅是短暂有效的，尽管有显著的初始反应，但晚期疾病患者通常会产生耐药性。越来越多的证据表明，抗凋亡蛋白，包括凋亡抑制蛋白（IAP）家族的蛋白，在化疗耐药中起重要作用。最近出现了阻断IAP功能的化合物。在这里，我们评估了AT-406，一种新的和口服活性拮抗剂的多种IAP蛋白，在卵巢癌细胞作为一个单一的代理，并在与卡铂的治疗效果和作用机制的组合。我们证明，AT-406在60%的体外检测的人卵巢癌细胞系中具有显著的单药活性，并在体内抑制卵巢癌进展，五分之三的卡铂耐药细胞系对AT-406敏感，突出了AT-406对固有或获得性铂耐药患者的治疗潜力。此外，我们的体内研究表明，AT-406增强了卡铂诱导的卵巢癌细胞死亡，并增加了实验小鼠的存活率，这表明AT-406使这些细胞对卡铂的反应敏感。从机制上讲，我们证明AT-406诱导的细胞凋亡与其下调XIAP的能力相关，而AT-406在AT-406敏感和抗性细胞系中诱导cIAP 1降解。总之，这些结果首次证明了AT-406作为单一药剂和与卡铂组合的抗卵巢癌功效，表明AT-406具有作为卵巢癌患者的新型疗法的潜力，特别是对于对基于铂的疗法表现出抗性的患者。
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 three out of five carboplatinresistant 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 downregulate XIAP whereas AT-406 induces cIAP 1 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.