Evaluating the Mechanism and Therapeutic Potential of PTC-028, a Novel Inhibitor of BMI-1 Function in Ovarian Cancer.
Evaluating the Mechanism and Therapeutic Potential of PTC-028, a Novel Inhibitor of BMI-1 Function in Ovarian Cancer.
复制标题
DOI：
10.1158/1535-7163.mct-17-0574
复制
发表时间：
2018-01
影响因子：
5.7
通讯作者：
Bhattacharya R
中科院分区：
文献类型：
--
作者：
Dey A;Xiong X;Crim A;Dwivedi SKD;Mustafi SB;Mukherjee P;Cao L;Sydorenko N;Baiazitov R;Moon YC;Dumble M;Davis T;Bhattacharya R
BMI-1，也称为干细胞因子，在几种恶性肿瘤中经常上调。BMI-1的高表达与不良预后相关，因此被认为是包括卵巢癌在内的许多恶性肿瘤的可行治疗靶点。认识到BMI-1的巨大病理学意义，最近正在开发针对BMI 1的小分子抑制剂。在目前的研究中，我们功能性地表征了PTC-028，一种通过翻译后修饰降低BMI-1水平的口服生物可利用化合物。我们报告说，PTC-028治疗在克隆生长和活力测定中选择性地抑制癌细胞，而正常细胞不受影响。从机制上讲，PTC-028介导的细胞BMI-1的过度磷酸化消耗加上ATP的同时时间减少和受损的线粒体氧化还原平衡增强了半胱天冬酶依赖性细胞凋亡。在卵巢癌原位小鼠模型中，口服单药PTC-028在体内表现出与标准顺铂/紫杉醇治疗相当的显著抗肿瘤活性。因此，PTC-028有可能作为一种有效的治疗药物，用于治疗选择有限的上皮性卵巢癌患者。
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 pathological significance of BMI-1, small molecule inhibitors against BMI1 are recently being developed. In the current study, we functionally characterize PTC-028, an orally bioavailable compound that decreases BMI-1 levels by post-translational modification We report that PTC-028 treatment selectively inhibits cancer cells in clonal growth and viability assays whereas normal cells remain unaffected. Mechanistically, hyper-phosphorylation 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 to 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.