Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, Catanzaro, Italy.
Department of Cardiovascular Disease, Tor Vergata University of Rome, Rome, Italy.
J Mol Cell Cardiol. 2018 Jun;119:10-18. doi: 10.1016/j.yjmcc.2018.04.007. Epub 2018 Apr 12.
Doxorubicin (DOXO) is one of the most widely used antineoplastic drugs. Despite its highly beneficial effects against several malignancies, the clinical use of DOXO is often associated to cardiomyopathy that leads to congestive heart failure. Here we investigated the antioxidant and cardioprotective effects of a polyphenol-rich fraction of citrus bergamot (BPF), in DOXO-induced cardiac damage in rats. Moreover, we evaluated the effect of BPF on cardiomyocyte survival and resident endogenous cardiac stem/progenitor cell (eCSC) activation. Adult male Wistar rats were i.p. injected with saline (serving as controls, CTRL, n = 10), BPF (20 mg/kg daily for 14 consecutive days, n = 10), DOXO (6 doses of 2,5 mg/Kg from day 1 to day 14, n = 10), and DOXO + BPF (n = 10). Animals were then sacrificed 7 days later (i.e., at 21 days). DOXO administration reduced cardiac function at 21 days, an adverse effect significantly attenuated in animals receiving DOXO + BPF. No changes were detected in rats receiving just saline or BPF alone. The cardioprotective effect of BPF on DOXO acute toxicity was also associated with a significant antioxidant effect coupled with protective autophagy restoration, and attenuation of cardiomyocyte apoptosis and reactive hypertrophy. Finally, treatment of rats with BPF prevented eCSCs attrition by DOXO which was followed by a limited but significant increase of newly-formed BrdU cardiomyocytes. In conclusion, BPF reduces DOXO-induced cardiotoxicity by counteracting reactive oxygen species (ROS) overproduction, thereby restoring protective autophagy and attenuating cardiomyocyte apoptosis and pathologic remodeling. This beneficial effects on the early toxicity of DOXO is associated with enhanced CSCs survival and regenerative potential. Overall these data point to a potential clinical role by diet supplementation with polyphenol-rich fraction of citrus bergamot in counteracting antracycline-induced cardiomyopathy.
多柔比星（DOXO）是最广泛使用的抗肿瘤药物之一。尽管它对多种恶性肿瘤具有高度有益的作用，但 DOXO 的临床应用常与导致充血性心力衰竭的心肌病相关。在这里，我们研究了富含佛手柑多酚的部分（BPF）对 DOXO 诱导的大鼠心脏损伤的抗氧化和心脏保护作用。此外，我们评估了 BPF 对心肌细胞存活和驻留的内源性心脏干细胞/祖细胞（eCSC）激活的影响。成年雄性 Wistar 大鼠腹腔注射生理盐水（作为对照，CTRL，n=10）、BPF（20mg/kg，连续 14 天，n=10）、DOXO（从第 1 天到第 14 天，每天 6 剂 2.5mg/Kg，n=10）和 DOXO+BPF（n=10）。然后，动物在 7 天后（即第 21 天）被处死。DOXO 给药在第 21 天降低了心脏功能，而在接受 DOXO+BPF 的动物中，这种不良作用明显减弱。仅接受生理盐水或 BPF 的大鼠未检测到变化。BPF 对 DOXO 急性毒性的心脏保护作用还与显著的抗氧化作用相关，该作用伴随着保护性自噬的恢复，以及心肌细胞凋亡和反应性肥大的减弱。最后，BPF 处理可防止 DOXO 引起的 eCSCs 损耗，随后新形成的 BrdU 心肌细胞数量有限但显著增加。总之，BPF 通过拮抗活性氧（ROS）的过度产生来减轻 DOXO 引起的心脏毒性，从而恢复保护性自噬并减弱心肌细胞凋亡和病理性重塑。这种对 DOXO 早期毒性的有益作用与增强 CSCs 的存活和再生潜力相关。总的来说，这些数据表明富含佛手柑多酚的部分饮食补充剂可能具有对抗蒽环类抗生素诱导的心肌病的临床作用。
