n-(1-3-benzodioxol-5-ylmethyl)-2-6-dichlorobenzamide and Cardiotoxicity

The use of doxorubicin (DOX) as an antineoplastic drug is compromised by its cardiotoxicity risk. Although several mechanisms have been proposed for DOX-induced cardiac dysfunction, there is still increased interest in assessing its effects. Likewise, it is important to find protocols that can prevent or minimize the side effects of DOX without hindering its antitumor activity. Thus, this study was designed to investigate the molecular mechanisms underlying DOX cardiotoxicity, with a special focus on cardiac energy metabolism and the ability of Alda-1 (ALDH2 agonist) to prevent DOX-induced cardiac alterations. We explored the effects of DOX on the histological morphology of the myocardium, on lipid profile, and on the expression of genes related to fatty acid metabolism, in the presence and absence of Alda-1 (8 mg/kg body weight; b.wt.). Two DOX treatment protocols were used: a single dose of DOX (4 mg/kg b.wt.); four doses of DOX (4 mg/kg b.wt.), one dose/week, for 4 weeks. Treatment with DOX caused a progressive injury in the cardiac tissue and an increase in the blood total cholesterol, high-density lipoproteins, very low-density lipoproteins and triglyceride, as well as an up-regulation of FABP4 (DOX and DOX + Alda-1 groups) and Slc27a2 (in DOX-treated animals). Alda-1 administration promoted reduction in the severity of the histopathological injuries (after single dose of DOX) and Slc27a2 overexpression was restored. In conclusion, the study revealed novel insights regarding the development of DOX-mediated cardiomyopathy, indicating a relationship between DOX exposure and FABP4 and Slc27a2 overexpression, and confirmed the cardioprotective effect of Alda-1.

Topics: Aldehyde Dehydrogenase, Mitochondrial; Animals; Benzamides; Benzodioxoles; Cardiotoxicity; Coenzyme A Ligases; Disease Models, Animal; Doxorubicin; Energy Metabolism; Fatty Acid-Binding Proteins; Gene Expression Profiling; Heart Diseases; Lipid Metabolism; Lipids; Male; Myocytes, Cardiac; Rats, Wistar; Transcriptome

Cyclophosphamide (CY)-induced acute cardiotoxicity is a common side effect which is dose dependent. It is reported that up to 20% of patients received high dose of CY treatment suffered from acute cardiac dysfunction. However, the effective intervention strategies and related mechanisms are still largely unknown. We aimed to investigate the effects of aldehyde dehydrogenase 2 (ALDH2), an important endogenous cardioprotective enzyme, on CY-induced acute cardiotoxicity and the underlying mechanisms. It was found that ALDH2 knockout (KO) mice were more sensitive to CY-induced acute cardiotoxicity, presenting as higher serum levels of creatine kinase-MB isoform and lactate dehydrogenase, and significantly reduced myocardial contractility compared with C57BL/6 (WT) mice. In addition, cardiac cell death, especially necrosis, was obviously increased in ALDH2 KO mice compared with WT mice after CY treatment. Furthermore, accumulation of toxic aldehydes such as acrolein and 4-HNE and reactive oxygen species (ROS) in the myocardium were significantly elevated after CY in ALDH2 KO mice. Importantly, ALDH2 activation by Alda-1 pretreatment markedly attenuated CY-induced accumulation of toxic aldehydes, cardiac cell death and cardiac dysfunction, without affecting CY's anti-tumor efficacy. In conclusion, the cardioprotective effects of ALDH2 activation against CY-induced acute cardiotoxicity are exerted via reducing toxic aldehydes accumulation and potentially interrupting the acrolein-ROS-aldehydes vicious circles, and thus alleviates myocardial cell death, without antagonizing the anti-tumor efficacy of CY. Therefore, ALDH2 might be a promising prevention and treatment target for CY-induced acute cardiotoxicity.

Topics: Acrolein; Aldehyde Dehydrogenase, Mitochondrial; Aldehydes; Animals; Apoptosis; Benzamides; Benzodioxoles; Cardiotoxicity; Cell Death; Cyclophosphamide; Humans; Inactivation, Metabolic; Mice; Mice, Knockout; Myocardium; Myocytes, Cardiac; Reactive Oxygen Species