Anti-Tumor Effect of Inhibition of DNA Damage Response Proteins, ATM and ATR, in Endometrial Cancer Cells
Anti-Tumor Effect of Inhibition of DNA Damage Response Proteins, ATM and ATR, in Endometrial Cancer Cells
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DOI：
10.3390/cancers11121913
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发表时间：
2019-12-01
期刊：
影响因子：
5.2
通讯作者：
Fujii, Tomoyuki
中科院分区：
文献类型：
--
作者：
Takeuchi, Makoto;Tanikawa, Michihiro;Fujii, Tomoyuki
虽然子宫内膜癌的发病率持续上升，但晚期或复发病例的治疗选择仍然有限，而且大多数病例对治疗有抗药性。许多化疗药物和放疗的抗肿瘤作用依赖于癌细胞DNA损伤的诱导；因此，DNA损伤反应（DDR）途径的激活被认为是影响耐药的重要因素。当某些DDR通路失活时，抑制其他DDR通路可诱导癌症特异性合成致死。因此，DDR通路被认为是癌症分子靶向治疗的有希望的候选者。交叉交叉的共济失调毛细血管扩张突变和Rad3相关和检查点激酶1 （ATR-Chk1）和共济失调毛细血管扩张突变和Rad3相关和检查点激酶2 （ATM-Chk2）通路是DNA损伤应答的主要途径。在这项研究中，我们通过评估ATM或ATR抑制剂与传统dna损伤治疗（多柔比星（DXR）、顺铂（CDDP）和照射）联合使用对子宫内膜癌细胞的影响，研究了这些途径抑制剂的体外抗肿瘤作用。两种抑制剂均增强了细胞对DXR、CDDP和辐照的敏感性。此外，ATR和Chk1抑制剂联合使用可诱导子宫内膜癌细胞DNA损伤，协同抑制细胞增殖。因此，这些靶向DNA损伤反应途径的分子疗法是治疗子宫内膜癌的新策略。
While the incidence of endometrial cancer continues to rise, the therapeutic options remain limited for advanced or recurrent cases, and most cases are resistant to therapy. The anti-tumor effect of many chemotherapeutic drugs and radiotherapy depends on the induction of DNA damage in cancer cells; thus, activation of DNA damage response (DDR) pathways is considered an important factor affecting resistance to therapy. When some DDR pathways are inactivated, inhibition of other DDR pathways can induce cancer-specific synthetic lethality. Therefore, DDR pathways are considered as promising candidates for molecular-targeted therapy for cancer. The crosstalking ataxia telangiectasia mutated and Rad3 related and checkpoint kinase 1 (ATR-Chk1) and ataxia telangiectasia mutated and Rad3 related and checkpoint kinase 2 (ATM-Chk2) pathways are the main pathways of DNA damage response. In this study, we investigated the anti-tumor effect of inhibitors of these pathways in vitro by assessing the effect of the combination of ATM or ATR inhibitors and conventional DNA-damaging therapy (doxorubicin (DXR), cisplatin (CDDP), and irradiation) on endometrial cancer cells. Both the inhibitors enhanced the sensitivity of cells to DXR, CDDP, and irradiation. Moreover, the combination of ATR and Chk1 inhibitors induced DNA damage in endometrial cancer cells and inhibited cell proliferation synergistically. Therefore, these molecular therapies targeting DNA damage response pathways are promising new treatment strategies for endometrial cancer.