Pillai Vinodkumar B, Kanwal Abhinav, Fang Yong Hu, Sharp Willard W, Samant Sadhana, Arbiser Jack, Gupta Mahesh P
Department of Surgery, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA.
Department of Medicine, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA.
Oncotarget. 2017 May 23;8(21):34082-34098. doi: 10.18632/oncotarget.16133.
Doxorubicin is the chemotherapeutic drug of choice for a wide variety of cancers, and cardiotoxicity is one of the major side effects of doxorubicin treatment. One of the main cellular targets of doxorubicin in the heart is mitochondria. Mitochondrial sirtuin, SIRT3 has been shown to protect against doxorubicin-induced cardiotoxicity. We have recently identified honokiol (HKL) as an activator of SIRT3, which protects the heart from developing pressure overload hypertrophy. Here, we show that HKL-mediated activation of SIRT3 also protects the heart from doxorubicin-induced cardiac damage without compromising the tumor killing potential of doxorubicin. Doxorubicin-induced cardiotoxicity is associated with increased ROS production and consequent fragmentation of mitochondria and cell death. HKL-mediated activation of SIRT3 prevented Doxorubicin induced ROS production, mitochondrial damage and cell death in rat neonatal cardiomyocytes. HKL also promoted mitochondrial fusion. We also show that treatment with HKL blocked doxorubicin-induced cardiac toxicity in mice. This was associated with reduced mitochondrial DNA damage and improved mitochondrial function. Furthermore, treatments of mice, bearing prostrate tumor-xenografts, with HKL and doxorubicin showed inhibition of tumor growth with significantly reduced cardiac toxicity. Our results suggest that HKL-mediated activation of SIRT3 protects the heart from doxorubicin-induced cardiotoxicity and represents a potentially novel adjunct for chemotherapy treatments.
阿霉素是多种癌症的首选化疗药物，心脏毒性是阿霉素治疗的主要副作用之一。阿霉素在心脏中的主要细胞靶点之一是线粒体。线粒体去乙酰化酶SIRT3已被证明可预防阿霉素诱导的心脏毒性。我们最近发现厚朴酚（HKL）是SIRT3的激活剂，可保护心脏免受压力超负荷肥大的影响。在此，我们表明HKL介导的SIRT3激活还可保护心脏免受阿霉素诱导的心脏损伤，而不会损害阿霉素的肿瘤杀伤潜力。阿霉素诱导的心脏毒性与活性氧生成增加以及随之而来的线粒体碎片化和细胞死亡有关。HKL介导的SIRT3激活可预防阿霉素诱导的大鼠新生心肌细胞中的活性氧生成、线粒体损伤和细胞死亡。HKL还促进线粒体融合。我们还表明，用HKL治疗可阻断阿霉素诱导的小鼠心脏毒性。这与线粒体DNA损伤减少和线粒体功能改善有关。此外，用HKL和阿霉素治疗携带前列腺肿瘤异种移植物的小鼠，显示出肿瘤生长受到抑制，心脏毒性显著降低。我们的结果表明，HKL介导的SIRT3激活可保护心脏免受阿霉素诱导的心脏毒性，代表了一种潜在的新型化疗辅助治疗方法。
