Abstract
Many studies have demonstrated that ursolic acid (UA) could potently inhibit the proliferation of a wide variety of cancer cells; however, its anti-tumor effect on multidrug resistant carcinoma was rarely reported. In the present study, UA exhibited cytotoxicity on the multidrug resistant human hepatoma cell line R-HepG2 with the IC50 value of 20 μM at 48 h. Our findings indicated that UA was not a binding substrate for P-glycoprotein and could not modulate the expression and activity of P-glycoprotein. This provides a possible mechanism on UA circumvention of the drug resistance. Mechanistic study demonstrated that UA induced apoptosis on R-HepG2 cells via both extrinsic and intrinsic apoptotic pathways, including the activation of caspase cascade and the release of cytochrome c and AIF from mitochondria to cytosol. Furthermore, in vivo study showed a significant inhibition on the growth of R-HepG2 cells in the UA-treated group (15 mg/kg/day, i.v.), with negligible damage towards the heart and the liver. The present study suggests the potential of UA as chemotherapeutic agent and provides further insight into the molecular basis of UA-induced apoptosis on multidrug resistance human hepatoma cells.
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