Thiolutin Alleviates Cardiotoxic Effects of Doxorubicin by Suppressing NLRP3 Inflammasome in the Mouse Model.

Abstract

Doxorubicin (DOX) has a limitation in clinical oncology due to its dose-dependent cardiotoxicity. Thiolutin (THL) can undermine DOX-induced cardiomyocyte injury by inhibiting the NLRP3 inflammasome activation, yet the efficacy of THL in DOX-induced cardiotoxicity (DOXIC) needs to be validated in animal models. DOX-induced mice were treated with THL to evaluate the efficacy of THL. Relative NLRP3 mRNA levels were determined by quantitative PCR. Blood samples were collected from diffuse large B-cell lymphoma (DLBCL) patients with or without DOXIC to validate serum levels of cTnT, IL-1β, CRP, BNP, and IL-18 by enzyme-linked immunosorbent assay. Apoptosis and pyroptosis-related protein levels were analyzed by western blot. Cardiac function and histopathological changes were determined by echocardiography, HE, Masson's, and wheat germ agglutinin staining. In clinical samples, NLRP3 mRNA and/or protein levels were also markedly heightened in peripheral blood mononuclear cells and serum samples from DOXIC patients, along with higher concentrations of IL-18, cTnT, and IL-1β. Importantly, cTnT possessed a positive correlation with NLRP3 mRNA, IL-1β, and IL-18. Moreover, cTnT possessed a positive correlation with NLRP3 mRNA, IL-1β, and IL-18 levels, suggesting a potential link between DOXIC and NLRP3 inflammasome. The outcomes demonstrated that THL reduced LVEF and LVFS, as well as elevated LVESD and LVEDD in DOX-challenged mice, accompanied by elevated serum concentrations of cTnT, CRP, and BNP. In addition, THL attenuated DOX-induced myocardial hypertrophy and cardiac fibrosis in mice, in conjunction with attenuation of DOX-induced upregulation of C-caspase3, Bax, NLRP3, C-caspase-1/Pro-caspase, GSDMD-N/GSDMD, IL-1β, and IL-18 in heart or serum samples. In conclusion, our data supported that THL alleviates the cardiotoxic effects of DOX and suppresses NLRP3 inflammasome in the mouse model, suggesting that THL as a potential drug for DOXIC.