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Abstract
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. Histopathology and transmission electron microscopy demonstrated apoptosis, autophagy, and necrosis corresponding to cytotoxicity in the tumor and cardioprotection in the heart. Changes in serum levels of 8-oxo-dG-modified DNA and total protein carbonylation corresponded to cardioprotective activity. Finally, 2D-electrophoresis/mass spectrometry identified specific serum proteins oxidized under cardiotoxic conditions. Our results demonstrate the utility of the SHR/SST-2 model and the potential of mitochondrially-directed agents to mitigate oxidative stress-induced cardiotoxicity. Our findings also emphasize the novel role of specific protein oxidation markers and autophagic mechanisms for cardioprotection.
Highlights
Many of the most commonly used anticancer agents induce cardiac toxicity as a dose-limiting side effect [1]
Anticancer therapies that are known to cause cardiac side effects originate from a wide array of drug classes, from anthracyclines such as the topoisomerase II poison doxorubicin to protein-based drugs such as interleukin-2 and trastuzumab [2,3]
Validation of the spontaneously hypertensive rats (SHRs)/SST-2 animal model The right mammary fat pad of each SHR was injected with approximately 56105 SST-2 cells
Summary
Many of the most commonly used anticancer agents induce cardiac toxicity as a dose-limiting side effect [1]. Because there is no welldefined predictor of whether an anticancer agent will induce cardiac toxicity while reducing tumor burden, often these deleterious side effects are only discovered late in the drug development process or after years of use in the clinic [4]. ROS-induced protein carbonylation is one of the most physiologically-relevant oxidative modifications of proteins because it marks affected proteins for proteosomal degradation [5]. The protein damage caused by oxidative stress is directly correlated with the increased number of carbonyl groups in proteins [6]. Dexrazoxane is an iron chelator that prevents oxidative stress and helps to mitigate the cardiotoxic effects of doxorubicin [8]. Dexrazoxane does not appear to affect the anticancer ability of doxorubicin in the clinic [9]
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