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Potential Therapeutic Strategies for Hypertension-Exacerbated Cardiotoxicity of Anticancer Drugs.

ABSTRACT: Despite their recognized cardiotoxic effects, anthracyclines remain an essential component in many anticancer regimens due to their superior antitumor efficacy. Epidemiologic data revealed that about one-third of cancer patients have hypertension, which is the most common comorbidity in cancer registries. The purpose of this review is to assess whether anthracycline chemotherapy exacerbates cardiotoxicity in patients with hypertension. A link between hypertension comorbidity and anthracycline-induced cardiotoxicity (AIC) was first suggested in 1979. Subsequent preclinical and clinical studies have supported the notion that hypertension is a major risk factor for AIC, along with the cumulative anthracycline dosage. There are several common or overlapping pathological mechanisms in AIC and hypertension, such as oxidative stress. Current evidence supports the utility of cardioprotective modalities as adjunct treatment prior to and during anthracycline chemotherapy. Several promising cardioprotective approaches against AIC pathologies include dexrazoxane, early hypertension management, and dietary supplementation of nitrate with beetroot juice or other medicinal botanical derivatives (e.g., visnagin and Danshen), which have both antihypertensive and anti-AIC properties. Future research is warranted to further elucidate the mechanisms of hypertension and AIC comorbidity and to conduct well-controlled clinical trials for identifying effective clinical strategies to improve long-term prognoses in this subgroup of cancer patients.

SUBMITTER: Kuriakose RK

PROVIDER: S-EPMC5086499 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Potential Therapeutic Strategies for Hypertension-Exacerbated Cardiotoxicity of Anticancer Drugs.

Kuriakose Robin K RK Kukreja Rakesh C RC Xi Lei L

Oxidative medicine and cellular longevity 20161017

Despite their recognized cardiotoxic effects, anthracyclines remain an essential component in many anticancer regimens due to their superior antitumor efficacy. Epidemiologic data revealed that about one-third of cancer patients have hypertension, which is the most common comorbidity in cancer registries. The purpose of this review is to assess whether anthracycline chemotherapy exacerbates cardiotoxicity in patients with hypertension. A link between hypertension comorbidity and anthracycline-in ...[more]

PMID: 27829985

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Project description:AimsTyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myelogenous leukaemia (CML). However, cardiotoxicity of these agents remains a serious concern. The underlying mechanism of these adverse cardiac effects is largely unknown. Delineation of the underlying mechanisms of TKIs associated cardiac dysfunction could guide potential prevention strategies, rescue approaches, and future drug design. This study aimed to determine the cardiotoxic potential of approved CML TKIs, define the associated signalling mechanism and identify potential alternatives.Methods and resultsIn this study, we employed a zebrafish transgenic BNP reporter line that expresses luciferase under control of the nppb promoter (nppb:F-Luciferase) to assess the cardiotoxicity of all approved CML TKIs. Our in vivo screen identified ponatinib as the most cardiotoxic agent among the approved CML TKIs. Then using a combination of zebrafish and isolated neonatal rat cardiomyocytes, we delineated the signalling mechanism of ponatinib-induced cardiotoxicity by demonstrating that ponatinib inhibits cardiac prosurvival signalling pathways AKT and extra-cellular-signal-regulated kinase (ERK), and induces cardiomyocyte apoptosis. As a proof of concept, we augmented AKT and ERK signalling by administration of Neuregulin-1β (NRG-1β), and this prevented ponatinib-induced cardiomyocyte apoptosis. We also demonstrate that ponatinib-induced cardiotoxicity is not mediated by inhibition of fibroblast growth factor signalling, a well-known target of ponatinib. Finally, our comparative profiling for the cardiotoxic potential of CML approved TKIs, identified asciminib (ABL001) as a potentially much less cardiotoxic treatment option for CML patients with the T315I mutation.ConclusionHerein, we used a combination of in vivo and in vitro methods to systematically screen CML TKIs for cardiotoxicity, identify novel molecular mechanisms for TKI cardiotoxicity, and identify less cardiotoxic alternatives.

Dataset Information

Potential Therapeutic Strategies for Hypertension-Exacerbated Cardiotoxicity of Anticancer Drugs.

Publications

Potential Therapeutic Strategies for Hypertension-Exacerbated Cardiotoxicity of Anticancer Drugs.

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