Modulation of DNA damage response and induction of apoptosis mediates synergism between doxorubicin and a new imidazopyridine derivative in breast and lung cancer cells
Modulation of DNA damage response and induction of apoptosis mediates synergism between doxorubicin and a new imidazopyridine derivative in breast and lung cancer cells
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DOI：
10.1016/j.dnarep.2015.10.004
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发表时间：
2016-01-01
期刊：
影响因子：
3.8
通讯作者：
Al-Tel, Taleb H.
中科院分区：
文献类型：
--
作者：
El-Awady, Raafat A.;Semreen, Mohammad H.;Al-Tel, Taleb H.
DNA 损伤反应机制（DDR）是癌症治疗的一个有吸引力的目标。 DDR 网络的调节可能会改变癌细胞对 DNA 损伤性抗癌药物（如阿霉素）的反应。本研究的目的是研究新开发的咪唑并吡啶 (IAZP) 衍生物在阿霉素诱导癌细胞 DNA 损伤后对 DDR 的影响。细胞毒性磺罗丹明-B 测定显示，IAZP 单独对六种癌细胞系（MCF7、A549、A549DOX11、HepG2、HeLa 和 M8）和正常成纤维细胞株具有微弱的抗增殖作用。 IAZP 与阿霉素的组合在肺癌 (A549) 和乳腺癌 (MCF7) 癌细胞中产生协同作用，但在其他癌细胞系和正常成纤维细胞中均未产生协同作用。分子研究表明，协同作用是通过调节 DNA 损伤反应和诱导细胞凋亡来介导的。使用恒定场凝胶电泳和免疫荧光检测 γ-H2AX 病灶，IAZP 被证明可以抑制 A549 和 MCF7 细胞中阿霉素诱导的 DNA 损伤的修复。免疫印迹分析表明，IAZP 抑制共济失调毛细血管扩张和 Rad3 相关 (ATR) 蛋白的磷酸化，后者在癌细胞对化疗引起的 DNA 损伤的反应中发挥着重要作用。此外，IAZP 增强了阿霉素诱导的 p21 降解、p53、CDK2、caspase 3/7 的激活以及 Rb 蛋白的磷酸化。这些作用增强了阿霉素诱导的两种细胞系的细胞凋亡。我们的结果表明，IAZP 是一种有前途的药物，可以通过靶向 DDR 来增强阿霉素对某些癌细胞的细胞毒作用。这是IAZP与抗癌药物联合临床应用的第一步，为开发针对DDR通路的化合物开辟了道路，从而提高抗癌药物的治疗指数并提高其治愈率。 (C) 2015 Elsevier B.V. 保留所有权利。
DNA damage response machinery (DDR) is an attractive target of cancer therapy. Modulation of DDR network may alter the response of cancer cells to DNA damaging anticancer drugs such as doxorubicin. The aim of the present study is to investigate the effects of a newly developed imidazopyridine (IAZP) derivative on the DDR after induction of DNA damage in cancer cells by doxorubicin. Cytotoxicity sulphrhodamine-B assay showed a weak anti-proliferative effect of IAZP alone on six cancer cell lines (MCF7, A549, A549DOX11, HepG2, HeLa and M8) and a normal fibroblast strain. Combination of IAZP with doxorubicin resulted in synergism in lung (A549) and breast (MCF7) cancer cells but neither in the other cancer cell lines nor in normal fibroblasts. Molecular studies revealed that synergism is mediated by modulation of DNA damage response and induction of apoptosis. Using constant-field gel electrophoresis and immunofluorescence detection of gamma-H2AX foci, IAZP was shown to inhibit the repair of doxorubicin-induced DNA damage in A549 and MCF7 cells. Immunoblot analysis showed that IAZP suppresses the phosphorylation of the ataxia lelangiectasia and Rad3 related (ATR) protein, which is an important player in the response of cancer cells to chemotherapy-induced DNA damage. Moreover, IAZP augmented the doxorubicin-induced degradation of p21, activation of p53, CDK2, caspase 3/7 and phosphorylation of Rb protein. These effects enhanced doxorubicin-induced apoptosis in both cell lines. Our results indicate that IAZP is a promising agent that may enhance the cytotoxic effects of doxorubicin on some cancer cells through targeting the DDR. It is a preliminary step toward the clinical application of IAZP in combination with anticancer drugs and opens the avenue for the development of compounds targeting the DDR pathway that might improve the therapeutic index of anticancer drugs and enhance their cure rate. (C) 2015 Elsevier B.V. All rights reserved.