Mito-Tempol and Dexrazoxane Exhibit Cardioprotective and Chemotherapeutic Effects through Specific Protein Oxidation and Autophagy in a Syngeneic Breast Tumor Preclinical Model

作者：Jennifer S. Dickey, Yanira González, Baikuntha Aryal, Steven Mog, Asako Nakamura, Christophe E. Redon, Ulrich Baxa, Elliot T. Rosen, Gang Cheng, Jacek Zielonka, Palak R. Parekh, Karen Mason, Joy Joseph, Balaraman Kalyanaraman, William Bonner, Eugene H. Herman, Emily Shacter, V. Ashutosh Rao · 发表于：PLoS ONE · 年份：2013 · DOI：10.1371/journal.pone.0070575 · 被引用次数：59 · 研究领域：Chemotherapy-induced cardiotoxicity and mitigation、Autophagy in Disease and Therapy、PARP inhibition in cancer therapy

Several front-line chemotherapeutics cause mitochondria-derived, oxidative stress-mediated cardiotoxicity. Iron chelators and other antioxidants have not completely succeeded in mitigating this effect. One hindrance to the development of cardioprotectants is the lack of physiologically-relevant animal models to simultaneously study antitumor activity and cardioprotection. Therefore, we optimized a syngeneic rat model and examined the mechanisms by which oxidative stress affects outcome. Immune-competent spontaneously hypertensive rats (SHRs) were implanted with passaged, SHR-derived, breast tumor cell line, SST-2. Tumor growth and cytokine responses (IL-1A, MCP-1, TNF-α) were observed for two weeks post-implantation. To demonstrate the utility of the SHR/SST-2 model for monitoring both anticancer efficacy and cardiotoxicity, we tested cardiotoxic doxorubicin alone and in combination with an established cardioprotectant, dexrazoxane, or a nitroxide conjugated to a triphenylphosphonium cation, Mito-Tempol (4) [Mito-T (4)]. As predicted, tumor reduction and cardiomyopathy were demonstrated by doxorubicin. We confirmed mitochondrial accumulation of Mito-T (4) in tumor and cardiac tissue. Dexrazoxane and Mito-T (4) ameliorated doxorubicin-induced cardiomyopathy without altering the antitumor activity. Both agents increased the pro-survival autophagy marker LC3-II and decreased the apoptosis marker caspase-3 in the heart, independently and in combination with doxorubicin. Histopath...