The Metabolic Inhibitor CPI-613 Negates Treatment Enrichment of Ovarian Cancer Stem Cells
The Metabolic Inhibitor CPI-613 Negates Treatment Enrichment of Ovarian Cancer Stem Cells
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DOI：
10.3390/cancers11111678
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发表时间：
2019-11-01
期刊：
影响因子：
5.2
通讯作者：
Rueda, Bo R.
中科院分区：
文献类型：
--
作者：
Bellio, Chiara;DiGloria, Celeste;Rueda, Bo R.
卵巢癌治疗中最重要的治疗挑战之一是复发性铂耐药疾病的发展。癌症干细胞（CSC）被认为有助于复发和铂耐药卵巢癌（OvCa）。选择性靶向CSC的药物可能会增加标准治疗细胞毒性药物，并有可能预防和/或延迟复发。相对于非CSC，CSC中对代谢途径调节的依赖性增加提供了可能的治疗机会。我们证明，相对于未处理的OvCa细胞，用代谢抑制剂CPI-613（devimistat，三羧酸（TCA）循环的抑制剂）在体外处理降低了CD 133+和CD 117+细胞频率，对非CSC细胞活力的影响可忽略不计。此外，在CPI-613处理的细胞中，体内球体形成能力和致瘤性降低。总的来说，这些结果表明用CPI-613治疗对卵巢CSC群体产生负面影响。此外，CPI-613阻止了奥拉帕尼或卡铂/紫杉醇治疗后CSC的非预期富集。总的来说，我们的研究结果表明CPI-613优先靶向卵巢CSC，并可能成为增强当前治疗策略的候选者，以延长OvCa的无进展生存期或总生存期。
One of the most significant therapeutic challenges in the treatment of ovarian cancer is the development of recurrent platinum-resistant disease. Cancer stem cells (CSCs) are postulated to contribute to recurrent and platinum-resistant ovarian cancer (OvCa). Drugs that selectively target CSCs may augment the standard of care cytotoxics and have the potential to prevent and/or delay recurrence. Increased reliance on metabolic pathway modulation in CSCs relative to non-CSCs offers a possible therapeutic opportunity. We demonstrate that treatment with the metabolic inhibitor CPI-613 (devimistat, an inhibitor of tricarboxylic acid (TCA) cycle) in vitro decreases CD133+ and CD117+ cell frequency relative to untreated OvCa cells, with negligible impact on non-CSC cell viability. Additionally, sphere-forming capacity and tumorigenicity in vivo are reduced in the CPI-613 treated cells. Collectively, these results suggest that treatment with CPI-613 negatively impacts the ovarian CSC population. Furthermore, CPI-613 impeded the unintended enrichment of CSC following olaparib or carboplatin/paclitaxel treatment. Collectively, our results suggest that CPI-613 preferentially targets ovarian CSCs and could be a candidate to augment current treatment strategies to extend either progression-free or overall survival of OvCa.