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Possible Susceptibility Genes for Intervention against Chemotherapy-Induced Cardiotoxicity.

ABSTRACT: Recent therapeutic advances have significantly improved the short- and long-term survival rates in patients with heart disease and cancer. Survival in cancer patients may, however, be accompanied by disadvantages, namely, increased rates of cardiovascular events. Chemotherapy-related cardiac dysfunction is an important side effect of anticancer therapy. While advances in cancer treatment have increased patient survival, treatments are associated with cardiovascular complications, including heart failure (HF), arrhythmias, cardiac ischemia, valve disease, pericarditis, and fibrosis of the pericardium and myocardium. The molecular mechanisms of cardiotoxicity caused by cancer treatment have not yet been elucidated, and they may be both varied and complex. By identifying the functional genetic variations responsible for this toxicity, we may be able to improve our understanding of the potential mechanisms and pathways of treatment, paving the way for the development of new therapies to target these toxicities. Data from studies on genetic defects and pharmacological interventions have suggested that many molecules, primarily those regulating oxidative stress, inflammation, autophagy, apoptosis, and metabolism, contribute to the pathogenesis of cardiotoxicity induced by cancer treatment. Here, we review the progress of genetic research in illuminating the molecular mechanisms of cancer treatment-mediated cardiotoxicity and provide insights for the research and development of new therapies to treat or even prevent cardiotoxicity in patients undergoing cancer treatment. The current evidence is not clear about the role of pharmacogenomic screening of susceptible genes. Further studies need to done in chemotherapy-induced cardiotoxicity.

SUBMITTER: Yang X

PROVIDER: S-EPMC7578723 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Possible Susceptibility Genes for Intervention against Chemotherapy-Induced Cardiotoxicity.

Yang Xinyu X Li Guoping G Yang Tao T Guan Manke M An Na N Yang Fan F Dai Qianqian Q Zhong Changming C Luo Changyong C Gao Yonghong Y Das Saumya S Xing Yanwei Y Shang Hongcai H Shang Hongcai H

Oxidative medicine and cellular longevity 20201013

Recent therapeutic advances have significantly improved the short- and long-term survival rates in patients with heart disease and cancer. Survival in cancer patients may, however, be accompanied by disadvantages, namely, increased rates of cardiovascular events. Chemotherapy-related cardiac dysfunction is an important side effect of anticancer therapy. While advances in cancer treatment have increased patient survival, treatments are associated with cardiovascular complications, including heart ...[more]

PMID: 33110473

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Project description:Sugemule-3 (SD) is a traditional Chinese medicine with protective effect of myocardium. However, the underlying mechanisms of the effect had not been elucidated.In the present study, the serum of SD was prepared. A model of β-adrenergic agonist isoprenaline (ISO)-induced H9c2 cardiomyocytes injury was established in vitro. The changes in cell viability were examined to determine the available concentration of ISO and serum of SD. ELISA, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay, and flow cytometry were used to detect the effect of serum of SD on oxidative stress and apoptosis. The expression levels of the mitochondria-dependent apoptotic pathway and mitogen-activated protein kinase signalling-related proteins were analyzed.Incubation with different dose of ISO (0.015, 0.01, 0.005, and 0.0025 mol/L) for 24 h caused dose-dependent loss of cell viability and 0.01 mol/L of ISO approximately reduced the cell viability to 50%. Pretreatment with 50 μ mol/L serum of SD effectively decreased the levels of ISO-induced cell toxicity. Serum of SD relived ISO-induced oxidative stress and apoptosis in H9c2 cardiomyocytes. A further mechanism study indicated that serum of SD inhibited the mitochondria-dependent apoptotic pathways and regulated the expression levels of Bcl-2 family. ISO activated ERK and P38, whereas serum of SD inhibited their activation.Serum of SD inhibits the ISO-induced activation of the mitochondria-dependent apoptotic pathway, oxidative stress, and ERK, P38 inactivation. Serum of SD is used for the treatment of ISO-induced cardiomyopathy.The serum of SD pretreatment significantly ameliorated ISO-induced H9c2 cardiomyocytes injuries.The protective effect related with apoptosis and oxidative stressInhibition of MAPK pathway was involed in serum of SD induced cardioprotection.The serum of SD is used for the treatment of ISO-induced cardiomyopathy. Abbreviations used: ELISA: Enzyme-linked Immunosorbent Assay; TUNEL: TdT-mediated dUTP nick end labeling; MTT: 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, DMSO: dimethyl sulfoxide; MDA: Malondialdehyde; SOD: Superoxide Dismutase; GSH-Px: Glutathione peroxidase.

Project description:BackgroundThe treatment of acute lymphoblastic leukemia (ALL) and osteosarcoma (OSC) is very effective: the vast majority of patients recover and survive for decades. However, they still need to face serious adverse effects of chemotherapy. One of these is cardiotoxicity which may lead to progressive heart failure in the long term. Cardiotoxicity is contributed mainly to the use of anthracyclines and might have genetic risk factors. Our goal was to test the association between left ventricular function and genetic variations of candidate genes.MethodsEchocardiography data from medical records of 622 pediatric ALL and 39 OSC patients were collected from the period 1989-2015. Fractional shortening (FS) and ejection fraction (EF) were determined, 70 single nucleotide polymorphisms (SNPs) in 26 genes were genotyped. Multivariate logistic regression and multi-adjusted general linear model were performed to investigate the influence of genetic polymorphisms on the left ventricular parameters. Bayesian network based Bayesian multilevel analysis of relevance (BN-BMLA) method was applied to test for the potential interaction of the studied cofactors and SNPs.ResultsOur results indicate that variations in ABCC2, CYP3A5, NQO1, SLC22A6 and SLC28A3 genes might influence the left ventricular parameters. CYP3A5 rs4646450 TT was 17% among ALL cases with FS lower than 28, and 3% in ALL patients without pathological FS (p = 5.60E-03; OR = 6.94 (1.76-27.39)). SLC28A3 rs7853758 AA was 12% in ALL cases population, while only 1% among controls (p = 6.50E-03; OR = 11.56 (1.98-67.45)). Patients with ABCC2 rs3740066 GG genotype had lower FS during the acute phase of therapy and 5-10 years after treatment (p = 7.38E-03, p = 7.11E-04, respectively). NQO1 rs1043470 rare T allele was associated with lower left ventricular function in the acute phase and 5-10 years after the diagnosis (p = 4.28E-03 and 5.82E-03, respectively), and SLC22A6 gene rs6591722 AA genotype was associated with lower mean FS (p = 1.71E-03), 5-10 years after the diagnosis.ConclusionsGenetic variants in transporters and metabolic enzymes might modulate the individual risk to cardiac toxicity after chemotherapy.

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Possible Susceptibility Genes for Intervention against Chemotherapy-Induced Cardiotoxicity.

Publications

Possible Susceptibility Genes for Intervention against Chemotherapy-Induced Cardiotoxicity.

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