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Anthracycline-free tumor elimination in mice leads to functional and molecular cardiac recovery from cancer-induced alterations in contrast to long-lasting doxorubicin treatment effects
Basic Research in Cardiology ( IF 9.5 ) Pub Date : 2021-10-20 , DOI: 10.1007/s00395-021-00902-7
Stefan Pietzsch 1 , Katharina Wohlan 2 , James T Thackeray 3 , Maren Heimerl 1 , Sven Schuchardt 4 , Michaela Scherr 5 , Melanie Ricke-Hoch 1 , Denise Hilfiker-Kleiner 1, 6
Affiliation  

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.



中文翻译:

与长效多柔比星治疗效果相比,小鼠中无蒽环类药物的肿瘤消除导致心脏功能和分子从癌症诱导的改变中恢复

晚期癌症对心脏的全身影响会导致心脏萎缩和功能障碍。本研究使用小鼠黑色素瘤模型(用更昔洛韦 (GCV) 诱导的自杀基因稳定转导的 B16F10 黑色素瘤细胞),分析了使用或不使用多柔比星 (Dox) 的癌症诱导的心肌病的恢复潜力。在无 Dox 肿瘤消除和恢复 70 ± 5 天后,癌症诱导的形态、功能、代谢和分子变化在先前携带肿瘤的小鼠中基本上是可逆的。此外,对血管紧张素 II 诱导的高血压的握力和心脏反应与健康对照小鼠相当。反过来,与单独使用 GCV 诱导的恢复相比,向携带黑色素瘤的小鼠添加 Dox(12 mg/kg BW)会降低急性期的​​存活率,而对心脏形态和功能恢复的长期影响是相似的。然而,Dox 治疗与心脏基因表达模式的永久性变化有关,尤其是与 DNA 损伤修复系统相关的昼夜节律通路。因此,在无化疗肿瘤消除后,心脏可以从癌症引起的损伤中恢复。相比之下,心脏毒性药物 Dox 的治疗除了众所周知的不良急性反应外,还会引起心脏的长期亚临床变化,尤其是生物钟基因。由于已知生物钟会影响心脏修复机制,这些变化可能会使心脏在一生中对额外的压力更加敏感,这至少在一定程度上可能导致晚期心脏毒性。Dox 治疗与心脏基因表达模式的永久性变化有关,尤其是与 DNA 损伤修复系统相关的昼夜节律通路。因此,在无化疗肿瘤消除后,心脏可以从癌症引起的损伤中恢复。相比之下,心脏毒性药物 Dox 的治疗除了众所周知的不良急性反应外,还会引起心脏的长期亚临床变化,尤其是生物钟基因。由于已知生物钟会影响心脏修复机制,这些变化可能会使心脏在一生中对额外的压力更加敏感,这至少在一定程度上可能导致晚期心脏毒性。Dox 治疗与心脏基因表达模式的永久性变化有关,尤其是与 DNA 损伤修复系统相关的昼夜节律通路。因此,在无化疗肿瘤消除后,心脏可以从癌症引起的损伤中恢复。相比之下,心脏毒性药物 Dox 的治疗除了众所周知的不良急性反应外,还会引起心脏的长期亚临床变化,尤其是生物钟基因。由于已知生物钟会影响心脏修复机制,这些变化可能会使心脏在一生中对额外的压力更加敏感,这至少在一定程度上可能导致晚期心脏毒性。因此,在无化疗肿瘤消除后,心脏可以从癌症引起的损伤中恢复。相比之下,心脏毒性药物 Dox 的治疗除了众所周知的不良急性反应外,还会引起心脏的长期亚临床变化,尤其是生物钟基因。由于已知生物钟会影响心脏修复机制,这些变化可能会使心脏在一生中对额外的压力更加敏感,这至少在一定程度上可能导致晚期心脏毒性。因此,在无化疗肿瘤消除后,心脏可以从癌症引起的损伤中恢复。相比之下,心脏毒性药物 Dox 的治疗除了众所周知的不良急性反应外,还会引起心脏的长期亚临床变化,尤其是生物钟基因。由于已知生物钟会影响心脏修复机制,这些变化可能会使心脏在一生中对额外的压力更加敏感,这至少在一定程度上可能导致晚期心脏毒性。

更新日期:2021-10-21
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