Amelioration effect of Egyptian sweet orange hesperidin on Ehrlich ascites carcinoma (EAC) bearing mice.

There are global increased interests to identify novel agents that can possess anti-tumor effects or maximize the anti-tumor effects of low doses for conventional anti-cancer drugs. The aim of this study was to investigate anti-tumor effects and protective role of isolated hesperidin from sweet orange on doxorubicin-induced toxicity in Ehrlich ascites carcinoma (EAC) bearing mice. Tumor cells were injected into Swiss albino mice followed by hesperidin administration either alone or in combination with doxorubicin. Biochemical parameters on serum and hepatic were measured. In addition, the effect of hesperidin on apoptotic genes (Caspase3 and Bax) and anti-apoptotic gene (Bcl2) on tumor cells were evaluated by RT- PCR. The results showed that addition of hesperidin to doxorubicin-induced higher anti-tumor responses than treatment with hesperidin or doxorubicin alone. Hesperidin and doxorubicin in combination prolonged the life span of EAC tumor-bearing mice which was associated with a decrease in the number of viable tumor cells and increases in dead tumor cells number. In addition, co-administration of hesperidin with doxorubicin ameliorated the alteration in serum ALT, AST, ALP, GGT and LDH activities, total protein, albumin, creatinine, urea and total lipids concentrations. Moreover, hesperidin alone and in combination with doxorubicin-treated group decreased hepatic, TBARS level significantly as compared with tumor bearing mice and doxorubicin treated group. In contrast, hesperidin alone and combined with doxorubicin ameliorated total antioxidant capacity, reduced glutathione level, and antioxidant enzymes activities such as GPx and CAT in liver tissues. Moreover, hesperidin induced apoptosis of tumor cells which appeared as DNA fragmentation by down-regulation of Bcl2 as anti-apoptotic gene and stimulation of Caspase3 and Bax genes expression as apoptotic genes. In conclusion, Egyptian citrus peels are a rich source of the antioxidant hesperidin. Moreover, it can ameliorate the cytotoxic effect of doxorubicin while enhancing its anti-tumor effect.