Identification of Chaetocin as a Potent non-ROS-mediated Anticancer Drug Candidate for Gastric Cancer
Identification of Chaetocin as a Potent non-ROS-mediated Anticancer Drug Candidate for Gastric Cancer
复制标题
鉴定毛壳素作为有效的非 ROS 介导的胃癌候选抗癌药物
DOI：
10.7150/jca.32803
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发表时间：
2019-01-01
影响因子：
3.9
通讯作者：
Zhan, Yan-yan
中科院分区：
文献类型：
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作者：
Liao, Xinwen;Fan, Yaqiong;Zhan, Yan-yan
毛壳素是从毛壳属植物中提取的天然产物，对多种肿瘤具有抗癌作用。然而，目前尚不清楚毛壳素的潜在适应症是否也包括人类胃癌。我们发现，毛壳素在人胃癌细胞系中诱导 caspase 依赖性和非依赖性细胞凋亡，这在很大程度上依赖于 BID 介导的 AIF 易位。尽管毛壳素没有增加胃癌细胞的细胞间ROS水平，但可能通过调节Bcl-2和BAX的表达而导致线粒体膜电位降低。毛壳素还可以诱导胃癌细胞自噬；氯喹阻断自噬增强了毛壳素的细胞毒性。进一步发现毛壳素可以抑制裸鼠胃癌异种移植物的生长。因此，我们的研究首次证明毛壳素对胃癌具有抗癌功效，毛壳素与自噬抑制剂联合使用可能会增强胃癌的治疗效果。由于长期且过高的 ROS 水平会引发耐药性，毛壳素可以在不增加 ROS 水平的情况下根除胃癌细胞，可能会启动一系列新的非 ROS 介导的抗肿瘤策略。
Chaetocin, a natural product extracted from Chaetomium species, possesses anticancer effects in several kinds of tumors. However, it remains unclear whether the potential indication for chaetocin could also include human gastric cancer. We found here that chaetocin induced caspase-dependent and -independent apoptosis in human gastric cancer cell lines, which greatly depended on BID-mediated AIF translocation. Despite not increasing the intercellular ROS levels in gastric cancer cells, chaetocin did cause a reduction in mitochondrial membrane potential probably through its regulation on the expression of Bcl-2 and BAX. Chaetocin could also induce autophagy in gastric cancer cells; blocking autophagy by chloroquine enhanced the cytotoxicity of chaetocin. Chaetocin was further found to suppress the growth of gastric cancer xenograft in nude mice. Therefore, our study provides first evidence that chaetocin has an anticancer efficacy against gastric cancer and the combined use of chaetocin with autophagy inhibitors may enhance the therapeutic effect for gastric cancer. As chronic and exorbitant ROS levels instigate drug resistance, chaetocin, which eradicates gastric cancer cells without increasing ROS levels, may initiate a new line of non-ROS-mediated anti-tumor strategy.