Perifosine induces cell cycle arrest and apoptosis in human hepatocellular carcinoma cell lines by blockade of Akt phosphorylation |
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Authors: | Hong-rong Fei Geng Chen Jian-mei Wang Feng-ze Wang |
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Institution: | (1) College of Pharmacology, Taishan Medical University, Chang Cheng Road, Taian, 271016, People’s Republic of China;(2) Department of Biology, Taishan Medical University, Chang Cheng Road, Taian, 271016, People’s Republic of China; |
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Abstract: | 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 G2 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. |
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Keywords: | Hepatocellular carcinoma Perifosine PI3 K/Akt Apoptosis Caspase Bcl-2 |
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