BMI-1, also known as a stem cell factor, is frequently upregulated in several malignancies. Elevated expression of BMI-1 correlates with poor prognosis and is therefore considered a viable therapeutic target in a number of malignancies including ovarian cancer. Realizing the immense pathologic significance of BMI-1, small-molecule inhibitors against BMI-1 are recently being developed. In this study, we functionally characterize PTC-028, an orally bioavailable compound that decreases BMI-1 levels by posttranslational modification. We report that PTC-028 treatment selectively inhibits cancer cells in clonal growth and viability assays, whereas normal cells remain unaffected. Mechanistically, hyperphosphorylation-mediated depletion of cellular BMI-1 by PTC-028 coupled with a concurrent temporal decrease in ATP and a compromised mitochondrial redox balance potentiates caspase-dependent apoptosis. In vivo, orally administered PTC-028, as a single agent, exhibits significant antitumor activity comparable with the standard cisplatin/paclitaxel therapy in an orthotopic mouse model of ovarian cancer. Thus, PTC-028 has the potential to be used as an effective therapeutic agent in patients with epithelial ovarian cancer, where treatment options are limited. Mol Cancer Ther; 17(1); 39–49. ©2017 AACR.

中文翻译：

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评估 PTC-028（一种新型 BMI-1 功能抑制剂）在卵巢癌中的作用机制和治疗潜力

BMI-1，也称为干细胞因子，在多种恶性肿瘤中经常上调。BMI-1 表达升高与预后不良相关，因此被认为是包括卵巢癌在内的多种恶性肿瘤的可行治疗靶点。认识到 BMI-1 的巨大病理意义，最近正在开发针对 BMI-1 的小分子抑制剂。在这项研究中，我们对 PTC-028 进行了功能表征，这是一种口服生物可利用的化合物，可通过翻译后修饰降低 BMI-1 水平。我们报告说，PTC-028 治疗在克隆生长和活力测定中选择性抑制癌细胞，而正常细胞不受影响。从机制上讲，PTC-028 过度磷酸化介导的细胞 BMI-1 消耗，加上 ATP 的暂时减少和线粒体氧化还原平衡受损，增强了 caspase 依赖性细胞凋亡。在体内，口服 PTC-028 作为单一药物，在卵巢癌原位小鼠模型中表现出与标准顺铂/紫杉醇疗法相当的显着抗肿瘤活性。因此，PTC-028 有潜力用作治疗选择有限的上皮性卵巢癌患者的有效治疗剂。摩尔癌症治疗；17(1)；39-49。©2017 AACR。