Resveratrol reverses doxorubicin-resistance and alleviates doxorubicin-induced myocardial injury in hepatocellular carcinoma.

BACKGROUND: Doxorubicin (DOX) chemotherapy for hepatocellular carcinoma is hampered by tumor multidrug resistance and cumulative cardiotoxicity. Resveratrol (RES), a natural polyphenol with anti-tumor and antioxidant effects, may reverse DOX resistance and mitigate myocardial injury. OBJECTIVE: To investigate whether RES reverses DOX resistance and boosts anti-tumor activity in HepG2-R/SMMC-7721-R cells via apoptosis and EMT regulation, while protecting H9c2 cardiomyocytes; an H22 tumor-bearing mouse model was used to confirm the dual in vivo efficacy of combined RES + DOX therapy. METHODS: In vitro, CCK-8, morphology observation, wound-healing, Transwell and TUNEL assays detected cell proliferation, migration and apoptosis. Western blot measured apoptosis- and EMT-related proteins. Intracellular ROS, SOD and MDA were tested to clarify antioxidant cardioprotective mechanisms. In vivo, tumor volume, body weight, serum myocardial injury biomarkers (CK-MB, cTnI, BNP), oxidative-stress indicators, as well as H&E and Masson´s trichrome staining of myocardial tissue were detected to assess treatment efficacy and safety. RESULTS: DOX monotherapy barely inhibited resistant cell growth, while RES alone exerted weak anti-tumor activity; RES + DOX exerted obvious combined cytotoxicity to suppress proliferation, metastasis and induce tumor apoptosis. RES reversed EMT and enhanced the activation of Bax/Bcl-2/caspase-3 signaling. In H9c2 cells, RES eliminated DOX-triggered ROS overload, restored SOD, lowered MDA and suppressed cardiomyocyte apoptosis. In vivo, the combination achieved optimal tumor suppression, reversed DOX-induced weight loss, normalized serum cardiac-specific damage biomarkers and myocardial oxidative stress. Histological examinations demonstrated that RES alleviated DOX-provoked myocardial structural damage and interstitial fibrosis, and RES itself showed no intrinsic cardiac toxicity. CONCLUSION: RES reverses DOX resistance and enhances anti-tumor effects; this finding is associated with the regulation of apoptosis and EMT signaling, and alleviates DOX-mediated cardiomyocyte oxidative injury through antioxidant pathways. This dual-action adjuvant strategy widens DOX´s therapeutic window for DOX-resistant hepatocellular carcinoma.