Inhibition of autophagy by chloroquine potentiates synergistically anti-cancer property of artemisinin by promoting ROS dependent apoptosis
Inhibition of autophagy by chloroquine potentiates synergistically anti-cancer property of artemisinin by promoting ROS dependent apoptosis
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DOI：
10.1016/j.biochi.2014.10.001
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发表时间：
2014-12-01
期刊：
影响因子：
3.9
通讯作者：
Chakrabarti, Gopal
中科院分区：
文献类型：
--
作者：
Ganguli, Arnab;Choudhury, Diptiman;Chakrabarti, Gopal
青蒿素（ART）是一种众所周知的抗疟疾药物，最近被证明可以选择性地杀死癌细胞。但效力低使其不适合用作抗癌药物。在这项研究中，我们调节 ART 诱导的自噬以提高 ART 作为抗癌药物的效力。 ART 降低了非小细胞肺癌 (A549) 细胞的细胞活力和集落形成能力，并且对正常肺 (WI38) 细胞无毒性。 ART 在治疗早期诱导自噬。氯喹（CQ）预处理和随后的ART治疗对于细胞死亡具有协同组合指数（CI）。 CQ 预处理对自噬的抑制导致酸性液泡 (AVO) 的积累，该液泡与未加工的损伤线粒体相结合，随后促进 ROS 生成，并导致细胞质中 Cyt C 的释放，导致 ART 处理的 A549 细胞中 caspase-3 依赖性细胞凋亡。抗氧化剂 N-乙酰半胱氨酸 (NAC) 清除 ROS 会抑制 caspase-3 活性，使细胞免于凋亡。在其他癌细胞 SCC25 和 MDA-MB-231 中也观察到类似的效果。使用 CQ 适当地操纵自噬提供了增强 ART 选择性抗癌特性的效力的强大策略。 (C) 2014 年 Elsevier B.V. 和法国生物化学与生物学分子公司 (SFBBM)。版权所有。
Artemisinin (ART) is a well-known anti-malarial drug, and recently it is shown prospective to selectively kill cancer cells. But low potency makes it inappropriate for use as an anticancer drug. In this study, we modulated the ART-induced autophagy to increase Potency of ART as an anticancer agent. ART reduced the cell viability and colony forming ability of non-small lung carcinoma (A549) cells and it was non-toxic against normal lung (WI38) cells. ART induced autophagy at the early stage of treatment. Pre-treatment with chloroquine (CQ) and followed by ART treatment had synergistic combination index (CI) for cell death. Inhibition of autophagy by CQ pre-treatment led to accumulation of acidic vacuoles (AVOs) which acquainted with unprocessed damage mitochondria that subsequently promoted ROS generation, and resulted releases of Cyt C in cytosol that caused caspase-3 dependent apoptosis cell death in ART-treated A549 cells. Scavenging of ROS by antioxidant N-acetyl-cysteine (NAC) inhibited caspase-3 activity and rescued the cells from apoptosis. Similar effects were observed in other cancer cells SCC25 and MDA-MB-231. The appropriate manipulation of autophagy by using CQ provides a powerful strategy to increase the Potency of selective anticancer property of ART. (C) 2014 Elsevier B.V. and Societe francaise de biochimie et biologie Moleculaire (SFBBM). All rights reserved.