Ellagic acid synergistically potentiates inhibitory activities of chemotherapeutic agents to human hepatocellular carcinoma.

Abstract

BACKGROUND\nHepatocellular carcinoma (HCC) is one of the most common malignant tumors with poor prognosis. Various chemotherapeutics are used in treatment of HCC, but most of them have significant toxicity to patients. Thus, it is urgently needed to develop new therapeutic strategies to achieve high specificity and tolerable adverse effects. As a natural polyphenol, ellagic acid (EA) demonstrates inhibitory effects in cancers.\n\n\nPURPOSE\nThe goal of the present study to investigate the anticancer activity of EA with a focus on its stimulating effects on doxorubicin hydrochloride (DOX) and cisplatin (DDP) in HCC treatment.\n\n\nMETHODS\nHepG2, SMMC-7721 and HL-7702 cells were treated with EA, DOX, DDP or their combinations. Cell viability and apoptosis were examined to evaluate the cytotoxicity of these treatments. Western blot analysis and immunofluorescent assays were used to determine expression of genes related to the mitochondrial apoptosis pathway. To assess the anticancer activities and systemic toxicity of EA, DOX and EA+DOX treatments, a xenograft mouse model with inoculated HepG2 cells was employed, followed by immunohistochemical and histopathological evaluation.\n\n\nRESULTS\nEA could both markedly potentiate anticancer activities of DOX and DDP to HCC HepG2 and SMMC-7721 cells, and reduce their cytotoxicity to normal liver HL-7702 cells. EA and its combination with DOX or DDP induced cell apoptosis through a pathway mediated by mitochondrial cytochrome c release. In nude mice, EA combination with a relatively low dosage of DOX effectively inhibited tumor growth without causing cardiotoxicity observed in mice treated by a high dosage of DOX.\n\n\nCONCLUSION\nWe discovered that EA synergistically potentiated DOX and DDP in suppressing HCC with significantly reduced side effects and this may represent a novel strategy in HCC therapies with both high anticancer efficiencies and low systemic toxicity in patients.