Genistein Potentiates the Effect of Arsenic Trioxide Against Human Hepatocellular Carcinoma: Role of Akt and Nuclear Factor-κB

Hepatocellular carcinoma (HCC) is a highly lethal malignancy mostly because of de novo and acquired resistance to conventional chemotherapy. Constitutive activation of Akt and nuclear factor-κB (NF-κB) represent major cellular abnormalities associated with both the pathogenesis and therapeutic resistance of HCC. The aim of the present study was to determine whether genistein, a natural Akt/NF-κB inhibitor, could enhance the anti-HCC efficacy of ATO both in vitro and in vivo. Our results demonstrated that genistein not only potentiated the proliferation-inhibiting and apoptosis-inducing effect of ATO on human HCC cell lines in vitro, but also dramatically augmented its suppressive effect on both tumor growth and angiogenesis in nude mice. The mechanism is at least partially due to the suppressive effect of genistein both on the proper and ATO-induced Akt activation, and on the activity of NF-κB, and the latter correlated with the suppression of NF-κB regulated gene products, including cyclin D1, Bcl-xL, Bcl-2, c-myc, COX-2, and VEGF. These data suggest that the combination of ATO with genistein presents a promising therapeutic approach for the treatment of HCC.