Pyrrolidine dithiocarbamate reverses Bcl-xL-mediated apoptotic resistance to doxorubicin by inducing paraptosis
Pyrrolidine dithiocarbamate reverses Bcl-xL-mediated apoptotic resistance to doxorubicin by inducing paraptosis
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DOI：
10.1093/carcin/bgy003
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发表时间：
2018-03-01
期刊：
影响因子：
4.7
通讯作者：
Choi, Kyeong Sook
中科院分区：
文献类型：
--
作者：
Park, Seok Soon;Lee, Dong Min;Choi, Kyeong Sook
癌细胞中Bcl-xL表达的升高有助于多柔比星（DOX）抗性，导致化疗失败。此外，高剂量阿霉素（DOX）在癌症治疗中的临床使用受到心脏毒性和肝毒性问题的限制。在这里，我们表明，与吡咯烷二硫代氨基甲酸酯（PDTC）的共同治疗减弱了阿霉素诱导的细胞凋亡，在Chang-L肝细胞和人肝细胞，但克服了阿霉素耐药性的Bcl-xL-过表达Chang-L细胞和几个肝细胞癌（HCC）细胞系与高Bcl-xL表达。此外，与任一种单药治疗相比，DOX和PDTC联合治疗显著延缓Huh-7 HCC细胞异种移植肿瘤模型中的肿瘤生长。这些结果表明，DOX/PDTC联合治疗可能提供一种安全有效的治疗策略，对恶性肝癌细胞Bcl-xL介导的凋亡缺陷。我们还发现，诱导的paraptosis，细胞死亡模式，伴随着内质网和线粒体的扩张，参与了这种抗癌作用的DOX/PDTC。DOX/PDTC处理过的Bcl-xL过表达的Chang-L细胞中细胞内谷胱甘肽水平降低，用巯基抗氧化剂预处理可有效阻断DOX/PDTC诱导的截瘫，但非巯基抗氧化剂不能。总的来说，我们的研究结果表明，巯基稳态的破坏可能是导致DOX/PDTC诱导的Bcl-xL过表达细胞的下垂的关键因素。
Elevated Bcl-xL expression in cancer cells contributes to doxorubicin (DOX) resistance, leading to failure in chemotherapy. In addition, the clinical use of high-dose doxorubicin (DOX) in cancer therapy has been limited by issues with cardiotoxicity and hepatotoxicity. Here, we show that co-treatment with pyrrolidine dithiocarbamate (PDTC) attenuates DOX-induced apoptosis in Chang-L liver cells and human hepatocytes, but overcomes DOX resistance in Bcl-xL-overexpressing Chang-L cells and several hepatocellular carcinoma (HCC) cell lines with high Bcl-xL expression. Additionally, combined treatment with DOX and PDTC markedly retarded tumor growth in a Huh-7 HCC cell xenograft tumor model, compared to either mono-treatment. These results suggest that DOX/PDTC co-treatment may provide a safe and effective therapeutic strategy against malignant hepatoma cells with Bcl-xL-mediated apoptotic defects. We also found that induction of paraptosis, a cell death mode that is accompanied by dilation of the endoplasmic reticulum and mitochondria, is involved in this anti-cancer effect of DOX/PDTC. The intracellular glutathione levels were reduced in Bcl-xL-overexpressing Chang-L cells treated with DOX/PDTC, and DOX/PDTC-induced paraptosis was effectively blocked by pretreatment with thiol-antioxidants, but not by non-thiol antioxidants. Collectively, our results suggest that disruption of thiol homeostasis may critically contribute to DOX/PDTC-induced paraptosis in Bcl-xL-overexpressing cells.