Quercetin potentiates doxorubicin mediated antitumor effects against liver cancer through p53/Bcl-xl.
Quercetin potentiates doxorubicin mediated antitumor effects against liver cancer through p53/Bcl-xl.
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槲皮素通过 p53/Bcl-xl 增强多柔比星介导的肝癌抗肿瘤作用
DOI：
10.1371/journal.pone.0051764
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Dong Q
中科院分区：
文献类型：
--
作者：
Wang G;Zhang J;Liu L;Sharma S;Dong Q
背景阿霉素（DOX）的剂量依赖性毒性限制了其临床应用，特别是在肝癌等耐药癌症中。在这项研究中，我们研究了槲皮素对DOX对肝癌细胞的抗肿瘤作用的作用及其对DOX介导的小鼠肝损伤的保护作用。方法与结果MTT法和Annexin V/PI染色法显示槲皮素选择性地增敏阿霉素诱导的肝癌细胞毒作用，同时保护正常肝细胞。槲皮素增加阿霉素介导的肝癌细胞凋亡是p53依赖性的，并通过下调Bcl-xl表达发生。Z-VAD-fastrin（半胱天冬酶抑制剂）、pifithrin-α（p53抑制剂）或过表达的Bcl-xl降低了槲皮素对DOX介导的凋亡的影响。槲皮素和DOX的联合治疗显著降低了小鼠肝癌移植瘤的生长。此外，槲皮素降低血清丙氨酸氨基转移酶和天冬氨酸氨基转移酶的水平增加，在DOX治疗的小鼠。槲皮素还能逆转阿霉素所致小鼠肝脏的病理改变。结论槲皮素在保护正常肝细胞的同时，增强了阿霉素对肝癌细胞的抗肿瘤作用。因此，槲皮素的开发可能有利于与DOX联合治疗，以提高对肝癌的治疗效果。
Background The dose-dependent toxicities of doxorubicin (DOX) limit its clinical applications, particularly in drug-resistant cancers, such as liver cancer. In this study, we investigated the role of quercetin on the antitumor effects of DOX on liver cancer cells and its ability to provide protection against DOX-mediated liver damage in mice. Methodology and Results The MTT and Annexin V/PI staining assay demonstrated that quercetin selectively sensitized DOX-induced cytotoxicity against liver cancer cells while protecting normal liver cells. The increase in DOX-mediated apoptosis in hepatoma cells by quercetin was p53-dependent and occurred by downregulating Bcl-xl expression. Z-VAD-fmk (caspase inhibitor), pifithrin-α (p53 inhibitor), or overexpressed Bcl-xl decreased the effects of quercetin on DOX-mediated apoptosis. The combined treatment of quercetin and DOX significantly reduced the growth of liver cancer xenografts in mice. Moreover, quercetin decreased the serum levels of alanine aminotransferase and aspartate aminotransferase that were increased in DOX-treated mice. Quercetin also reversed the DOX-induced pathological changes in mice livers. Conclusion and Significance These results indicate that quercetin potentiated the antitumor effects of DOX on liver cancer cells while protecting normal liver cells. Therefore, the development of quercetin may be beneficial in a combined treatment with DOX for increased therapeutic efficacy against liver cancer.
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影响因子：
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作者：
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