Topotecan synergizes with CHEK1 (CHK1) inhibitor to induce apoptosis in ovarian cancer cells.
Topotecan synergizes with CHEK1 (CHK1) inhibitor to induce apoptosis in ovarian cancer cells.
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DOI：
10.1186/s12885-015-1231-z
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发表时间：
2015-03-28
期刊：
影响因子：
3.8
通讯作者：
Annunziata CM
中科院分区：
文献类型：
--
作者：
Kim MK;James J;Annunziata CM
拓扑替康(TPT)是对铂耐药或难治性卵巢癌妇女的一种治疗选择。然而，TPT的剂量限制性毒性是骨髓抑制。这导致我们寻求一种联合治疗方法，以癌症靶向的方式增强TPT的抗癌活性。卵巢浆液性癌是卵巢癌的一个主要亚型，其DNA修复途径异常，常表现为细胞周期调节因子CHEK1(CHK1)的高水平表达和DNA损伤感受器。CHEK1抑制剂是一种新的治疗方法，已作为单一药物或联合化疗用于许多癌症。我们评估了TPT在一组高级别浆液性卵巢癌细胞(HGS)和非HGS卵巢癌细胞中的细胞效应。然后，我们测定了在CHEK1抑制剂PF477736存在和不存在的情况下TPT的IC50。根据细胞存活率分析计算TPT和PF477736之间的协同作用。用Caspase3/7活性测定、裂解PARP1和γH_2AX蛋白免疫印迹法比较联合用药的细胞毒作用和细胞凋亡活性。与HGS卵巢癌细胞相比，非HGS卵巢癌细胞对TPT治疗通常更敏感。当TPT与CHEK1抑制剂联合使用时，对HGS卵巢癌细胞的增殖具有明显的协同抑制作用。这种细胞毒性的戏剧性协同作用与细胞凋亡标志物的增加是一致的。我们的研究结果表明，CHEK1抑制剂的加入增加了卵巢癌细胞对TPT的反应。此外，减少剂量的两种药物通过TPT和CHEK1抑制剂的联合使用获得了最大的细胞毒作用。这一策略可能会将药物的副作用降至最低，从而延长临床益处。本文的在线版本(doi：10.1186/s12885-0151231-z)包含补充材料，授权用户可以使用。
Topotecan (TPT) is a therapeutic option for women with platinum-resistant or -refractory ovarian cancer. However, the dose-limiting toxicity of TPT is myelosuppression. This led us to seek a combination treatment to augment TPT anti-cancer activity in a cancer-targeted manner. Ovarian serous cancers, a major subtype, show dysregulated DNA repair pathway and often display a high level of CHEK1 (CHK1), a cell cycle regulator and DNA damage sensor. CHEK1 inhibitors are a novel approach to treatment, and have been used as single agents or in combination chemotherapy in many cancers. We evaluated the cellular effects of TPT in a panel of high grade serous (HGS) and non-HGS ovarian cancer cells. We then determined IC50s of TPT in the absence and presence of CHEK1 inhibitor, PF477736. Synergism between TPT and PF477736 was calculated based on cellular viability assays. Cytotoxic effect of the combined treatment was compared with apoptotic activities by Caspase3/7 activity assay and Western blotting of cleaved-PARP1 and γH2AX. Non-HGS ovarian cancer cells were generally more sensitive to TPT treatment compared to HGS ovarian cancer cells. When combined with CHEK1 inhibitor, TPT potently and synergistically inhibited the proliferation of HGS ovarian cancer cells. This dramatic synergism in cellular toxicity was consistent with increases in markers of apoptosis. Our findings suggest that the addition of CHEK1 inhibitor increases the response of ovarian cancer cells to TPT. Furthermore, reduced dosages of both drugs achieved maximal cytotoxic effects by combining TPT with CHEK1 inhibitor. This strategy would potentially minimize side effects of the drugs for extended clinical benefit. The online version of this article (doi:10.1186/s12885-015-1231-z) contains supplementary material, which is available to authorized users.
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