Ma Jing, Salamoun Joseph, Wipf Peter, Edwards Robert, Van Houten Bennett, Qian Wei
Department of Pharmacology and Chemical Biology, University of Pittsburgh, and UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA.
Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College of HuaZhong University of Science and Technology, Wuhan 430030, China.
Oncotarget. 2017 Dec 26;9(5):6042-6054. doi: 10.18632/oncotarget.23679. eCollection 2018 Jan 19.
Cancer stem cell-like cells (CSC-LCs) contribute to drug resistance and recurrence of ovarian cancer. Strategies that can eradicate CSC-LCs are expected to substantially improve the outcome of ovarian cancer treatment. We have previously identified a class of thioxodihydroquinazolinone small molecules, which have strong synergistic antitumor activity with platinum drugs, the standard chemotherapeutic agents for ovarian cancer treatment. In the current study, using the activity of aldehyde dehydrogenase (ALDH) as a marker of CSC-LCs, we demonstrated that the combination of thioxodihydroquinazolinone compound 19 with cisplatin is able to diminish ALDH-high CSC-LC populations in both platinum-resistant ovarian cancer cell lines and primary ovarian cancer cells from metastatic ascites of a cisplatin-resistant patient. Compound 19 enhanced the accumulation of intracellular cisplatin in ALDH-high ovarian CSC-LCs. The combination of compound 19 with cisplatin was also able to reduce the sphere-forming capability of cisplatin-resistant ovarian cancer cells. Using a spheroid-based metastasis model of ovarian cancer, we demonstrated that the co-administration of compound 19 with cisplatin prevents ovarian cancer spheroid cells from attaching to substratum and spreading. In a cisplatin-resistant intraperitoneal xenograft mouse model, the combination of compound 19 with cisplatin significantly reduced tumor burden, as compared to cisplatin alone. Taken together, our study demonstrated that thioxodihydroquinazolinones represent a new class of agents that in combination with cisplatin are capable of eliminating CSC-LCs in ovarian cancer. Further development of thioxodihydroquinazolinone small molecules may yield a more effective treatment for cisplatin-resistant metastatic ovarian cancer.
癌症干细胞样细胞（CSC-LCs）导致卵巢癌的耐药性和复发。有望根除CSC-LCs的策略将显著改善卵巢癌治疗的效果。我们之前已鉴定出一类硫代二氢喹唑啉酮小分子，它们与铂类药物（卵巢癌治疗的标准化疗药物）具有很强的协同抗肿瘤活性。在当前研究中，我们以醛脱氢酶（ALDH）的活性作为CSC-LCs的标志物，证明硫代二氢喹唑啉酮化合物19与顺铂联合使用能够减少铂耐药卵巢癌细胞系以及来自一名铂耐药患者转移性腹水的原发性卵巢癌细胞中ALDH高表达的CSC-LC群体。化合物19增强了顺铂在ALDH高表达的卵巢CSC-LCs中的细胞内蓄积。化合物19与顺铂联合使用还能够降低铂耐药卵巢癌细胞的成球能力。利用基于球体的卵巢癌转移模型，我们证明化合物19与顺铂共同给药可阻止卵巢癌球体细胞附着于基质并扩散。在铂耐药的腹腔异种移植小鼠模型中，与单独使用顺铂相比，化合物19与顺铂联合使用显著减轻了肿瘤负担。综上所述，我们的研究表明硫代二氢喹唑啉酮代表一类新型药物，与顺铂联合使用能够消除卵巢癌中的CSC-LCs。硫代二氢喹唑啉酮小分子的进一步研发可能会为铂耐药转移性卵巢癌带来更有效的治疗方法。
