Hepatocellular carcinoma (HCC) is one of the most common solid
cancers, representing the third cause of
cancer-related death among cirrhotic patients. Treatment of advanced HCC has become a very active area of research.
Perifosine, a new synthetic alkylphospholipid Akt inhibitor, has shown anti-
tumor activity by inhibition of Akt phosphorylation. In this study, the effect of
perifosine on the cell proliferation and apoptosis in
hepatoma cells has been investigated. Cell growth inhibition was detected by MTT assay, cell cycle was analyzed by flow cytometry, AnnexinV-
FITC apoptosis detection kit was used to detect cell apoptosis, and
protein expression was examined by Western blotting analysis. Our present studies showed that Akt phosphorylation was inhibited by
perifosine in HepG2 and Bel-7402 human
hepatocellular carcinoma cells.
Perifosine inhibited the growth of HepG2 cells and Bel-7402 cells in a dose-dependent manner, and arrested cell cycle progression at the G(2) phase. Apoptosis induction became more effective with increasing
perifosine concentration. The
caspase cascade and its downstream effectors,
Poly (ADP-ribose) polymerase (PARP), were also activated simultaneously upon
perifosine treatment. The proapoptotic effect of
perifosine was in part depending on regulation of the phosphorylation level of ERK and JNK.
Perifosine cotreatment substantially increased cytotoxic effects of
cisplatin in HepG2 cells. Down-regulating the expression of Bcl-2 and up-regulating the level of Bax may be the potential mechanism for this synergistic effect. Our findings suggest that the small molecule Akt inhibitor
perifosine shows substantial anti-
tumor activity in human
hepatoma cancer cell lines, and is a good candidate for treatment combinations with classical
cytostatic compounds in
hepatocellular carcinoma.