Abstract
Systemic effects of advanced cancer impact on the heart leading to cardiac atrophy and functional impairment. Using a murine melanoma cancer model (B16F10 melanoma cells stably transduced with a Ganciclovir (GCV)-inducible suicide gene), the present study analysed the recovery potential of cancer-induced cardiomyopathy with or without use of doxorubicin (Dox). After Dox-free tumor elimination and recovery for 70 ± 5 days, cancer-induced morphologic, functional, metabolic and molecular changes were largely reversible in mice previously bearing tumors. Moreover, grip strength and cardiac response to angiotensin II-induced high blood pressure were comparable with healthy control mice. In turn, addition of Dox (12 mg/kg BW) to melanoma-bearing mice reduced survival in the acute phase compared to GCV-alone induced recovery, while long-term effects on cardiac morphologic and functional recovery were similar. However, Dox treatment was associated with permanent changes in the cardiac gene expression pattern, especially the circadian rhythm pathway associated with the DNA damage repair system. Thus, the heart can recover from cancer-induced damage after chemotherapy-free tumor elimination. In contrast, treatment with the cardiotoxic drug Dox induces, besides well-known adverse acute effects, long-term subclinical changes in the heart, especially of circadian clock genes. Since the circadian clock is known to impact on cardiac repair mechanisms, these changes may render the heart more sensitive to additional stress during lifetime, which, at least in part, could contribute to late cardiac toxicity.
Highlights
Cancer and heart disease are major causes of death in western countries [46]
C, D Cardiomyocyte cross-sectional area (CSA) after wheat germ agglutinin (WGA) staining and hematoxilin/eosin staining in left ventricular cryosections in age-matched controls without cancer cell injection and without GCV treatment (PBS-m, n = 6), healthy age-matched controls without cancer cell injection and with GCV treatment (GCV-m, n = 6), tumorbearing mice with advanced tumor burden (HSVtk-m, n = 6), mice recovered from B16F10HSVtk-c-induced tumor burden after GCV treatment (Rec-m, n = 6) and mice recovered from B16F10HSVtkc-induced tumor burden after GCV treatment
Data are depicted as mean ± SD, **P < 0.01 vs. respective non-tumor group and ##P < 0.01 vs. respective non-GCV group using Log-rank Mantel-Cox test or two-way ANOVA followed by Bonferroni post hoc tests as required effects of cancer itself on the heart are less known
Summary
Cancer and heart disease are major causes of death in western countries [46]. Accumulating evidence suggests multiple pathophysiological interactions between cancer, anti-cancer therapies and heart failure [9, 41]. Anthracycline-induced cardiotoxicity represents a continuous phenomenon that includes increased oxidative stress, poisoning of topoisomerase 2b, DNA damage, mitochondrial and myocardial cell injury leading to progressive heart failure, that can be enhanced by additional cardiac stress stimuli such as extensive physical activity, pregnancy and untreated high blood pressure later in life [6, 33]. Both cancer disease and anti-cancer treatment induce alterations in signaling pathways and gene expression in the heart [22, 34, 39, 43]. The simultaneous impact of both conditions in the heart is barely studied since most experimental models study either cancer-induced effects or cancer therapy-induced damage separately
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