The dual functions of the pentacyclic triterpenoid madecassic acid in ameliorating doxorubicin-induced cardiotoxicity and enhancing the antitumor efficacy of doxorubicin.

IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY International Journal of Biological Sciences Pub Date : 2024-10-07 eCollection Date: 2024-01-01 DOI:10.7150/ijbs.97418
Wenlin Li, Kun Xu, Ming Lan, Junpeng Gao, Lin Dou, Yao Yang, Que Wang, Mingjing Yan, Sainan Li, Qinan Ma, Weimeng Tian, Beidong Chen, Ju Cui, Xiyue Zhang, Jianping Cai, Hua Wang, Liang Sun, Jian Li, Xiuqing Huang, Tao Shen
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Abstract

Doxorubicin (DOX) is an anthracycline that has excellent anticancer effects during tumor chemotherapy, but it can cause cardiotoxic effects and its clinical use has been limited. Therefore, finding new drugs or methods to prevent or reverse the cardiac damage caused by DOX therapy in cancer patients is essential. Previous studies have identified potential cardioprotective effects of Centella asiatica (C. asiatica), and madecassic acid (MA) is a pentacyclic triterpenoid derived from C. asiatica. However, the pharmacological effects of MA on the heart and tumors during tumor chemotherapy are not fully understood. The aim of this study was to investigate the pharmacological function and molecular mechanisms of MA in the heart and tumor during chemotherapy. In a DOX-induced acute heart failure mouse model and a cardiomyocyte injury model, MA reduced cardiomyocyte oxidative stress and the inflammatory response, improved mitochondrial function, and attenuated autophagic flux blockade and apoptosis. Interestingly, MA significantly increased the expression and activity of SIRT1. When SIRT1 was knocked down, the protective effect of MA on cardiomyocytes was significantly inhibited, suggesting that MA may exert cardioprotective effects through the SIRT1 pathway. Interestingly, in contrast to its cardioprotective effect, MA could synergize with DOX and significantly contribute to the anticancer chemotherapeutic effect of DOX by inhibiting proliferation, migration and invasion; promoting apoptosis; and suppressing tumor progression by inhibiting the expression of the DDX5 pathway in tumor cells. Here, we identified the pharmacological functions of the pentacyclic triterpenoid MA in ameliorating DOX-induced cardiotoxicity and enhancing the antitumor efficacy of DOX.

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五环三萜类化合物马德卡西酸在改善多柔比星诱导的心脏毒性和增强多柔比星抗肿瘤疗效方面的双重功能。
多柔比星(DOX)是一种蒽环类药物,在肿瘤化疗过程中具有极佳的抗癌效果,但它会引起心脏毒性反应,临床应用受到限制。因此,寻找新的药物或方法来预防或逆转 DOX 治疗对癌症患者造成的心脏损伤至关重要。之前的研究发现积雪草(Centella asiatica)具有潜在的心脏保护作用,而积雪草酸(MA)是从积雪草中提取的一种五环三萜类化合物。然而,MA 在肿瘤化疗过程中对心脏和肿瘤的药理作用还不完全清楚。本研究旨在探讨MA在化疗期间对心脏和肿瘤的药理作用和分子机制。在 DOX 诱导的急性心衰小鼠模型和心肌细胞损伤模型中,MA 可降低心肌细胞氧化应激和炎症反应,改善线粒体功能,减轻自噬通路阻断和细胞凋亡。有趣的是,MA 能明显提高 SIRT1 的表达和活性。当 SIRT1 被敲除时,MA 对心肌细胞的保护作用明显受到抑制,这表明 MA 可能通过 SIRT1 途径发挥心脏保护作用。有趣的是,与心肌保护作用不同,MA能与DOX协同作用,通过抑制肿瘤细胞的增殖、迁移和侵袭,促进细胞凋亡,以及抑制DDX5通路的表达来抑制肿瘤的进展,从而显著促进DOX的抗癌化疗作用。在此,我们确定了五环三萜类化合物 MA 在改善 DOX 诱导的心脏毒性和增强 DOX 抗肿瘤疗效方面的药理作用。
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来源期刊
International Journal of Biological Sciences
International Journal of Biological Sciences 生物-生化与分子生物学
CiteScore
16.90
自引率
1.10%
发文量
413
审稿时长
1 months
期刊介绍: The International Journal of Biological Sciences is a peer-reviewed, open-access scientific journal published by Ivyspring International Publisher. It dedicates itself to publishing original articles, reviews, and short research communications across all domains of biological sciences.
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