Arbutin as a promising cardioprotective anticancer adjuvant with doxorubicin in solid Ehrlich carcinoma through targeting NEK7-dependent inflammasome/SIRT1/caspase-3/oxidative stress pathways.

Abstract

Doxorubicin (DOX) is an effective cancer therapy; however, it causes a lethal dose and time-dependent cardiotoxicity. Many patients also have cardiovascular events due to cancer itself. Therefore, our objective was to examine the antitumor effect of the natural compound arbutin and its potential cardioprotective effects against cancer and DOX-induced cardiotoxicity. Solid Ehrlich carcinoma (SEC) was established in female Swiss albino mice. DOX was administered at a dose of 6 mg/kg, ip once weekly for 21 days. A dose of 50 mg/kg ip of arbutin was administered daily for 21 consecutive days. Both tumor and heart tissues were investigated. Our results indicated that arbutin effectively reduced tumor weight and volume, both when used alone or combined with DOX, by decreasing tumor malonaldehyde and increasing glutathione levels. They also lowered tumor Sirtuin 1 (SIRT1) and increased caspase-3 expression. Unlike DOX, arbutin suppressed tumor NLR-family pyrin domain containing 3 (NLRP3), NIMA-related kinase 7 (NEK7), caspase 1, and interleukin-1-beta (IL-1β) expressions. Moreover, arbutin reduced high cardiac marker levels and attenuated cardiotoxicity by decreasing the cardiac NLRP3, NEK7, caspases 1 and 3, and IL-1β, and increasing SIRT1 expressions. Therefore, arbutin may represent a promising antitumor drug or an adjuvant therapy in the SEC model to mitigate possible cardiac issues.