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

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.

Chemotherapy-Free Targeted Anti-BCR-ABL+ Acute Lymphoblastic Leukemia Therapy May Benefit the Heart

“…Thus, the heart is not able to recover from leukemia-induced cardiac damage and harbors long-lasting cardiac side effects under these conditions. In contrast to our data, a recently published study has demonstrated that a reversible murine cancer model using B16F10 melanoma-HSV-TK cells enabling melanoma-cell-specific chemotherapy-free elimination by GCV treatment showed cardiac recovery [ 46 ]. In addition, after cardiac recovery, all melanoma-induced phenotypic, metabolic, molecular and functional changes in the heart were almost reversible after GCV-mediated tumor elimination without evidence of a contribution to long-term cardiac damage [ 46 ].…”

“…In contrast to our data, a recently published study has demonstrated that a reversible murine cancer model using B16F10 melanoma-HSV-TK cells enabling melanoma-cell-specific chemotherapy-free elimination by GCV treatment showed cardiac recovery [ 46 ]. In addition, after cardiac recovery, all melanoma-induced phenotypic, metabolic, molecular and functional changes in the heart were almost reversible after GCV-mediated tumor elimination without evidence of a contribution to long-term cardiac damage [ 46 ]. These data clearly demonstrate that, depending on the type of cancer, different strong and long-lasting cardiac complications and adverse effects may occur.…”

Isoalantolactone Enhances the Antitumor Activity of Doxorubicin by Inducing Reactive Oxygen Species and DNA Damage

“…Doxorubicin is one of the most classical chemotherapeutics and has been extensively used for cancer therapy ( 3 , 4 ). However, drug resistance and serious side effects limited its further clinical application ( 5 , 6 ). Therefore, developing new therapeutic drugs that can effectively treat colon cancer is urgent and essential.…”

Cardiac dysfunction from cancer and cancer therapy: new pathways for the prevention of late cardiotoxicity

“…In cancer patients, cachexia with potential adverse consequences for cardiac integrity affects up to 74% of cancer patients, with significant consequences on long-term cardiovascular health [3]. Understanding the underlying pathomechanisms and their implications on acute and late cardiac dysfunction is crucial to optimize the management of cardio-oncology patients [6,15,18,23].…”

“…In this issue of Basic Research in Cardiology, Pietzsch and colleagues shed new light on the often neglected impact of the underlying cancer on the recovery after cancer-induced cardiomyopathy [ 16 ]. As a novel approach, the authors establish a reversible melanoma mouse model on the basis of the common B16F10 melanoma cell line that was genetically modified via lentiviral transduction of a suicide gene that could induce cell death upon exposure to ganciclovir.…”