Mechanism of apicidin-induced cell cycle arrest and apoptosis in Ishikawa human endometrial cancer cells.
Histone deacetylase (HDAC) inhibitors are a promising new class of anticancer agents that act by inhibiting cell proliferation and inducing apoptosis in a variety of cancer cells. Although apicidin acts as a potent HDAC inhibitor, the precise mechanism for its anti-tumor activity in human endometrial cancer cells is not completely understood. This study examined the anti-tumor effects of apicidin in Ishikawa cancer cells. The level of cell proliferation, the stage of the cell cycle, and apoptosis were measured after the apicidin treatment. Apicidin significantly inhibited the proliferation of Ishikawa cells in a dose-dependent manner. In addition, apicidin markedly up-regulated the p21(WAF1) and down-regulated the expression of cyclins (A, B1, D1, or E), and CDKs (2 or 4), which leading to cell cycle arrest. Cell cycle analysis showed that the apicidin treatment increased the proportion of cells in the G1 phase, and decreased the ratio of cells in the S phase in a dose-dependent manner. Apicidin significantly increased the sub-G1 population and the number of TUNEL positive apoptotic cells compared with the untreated control. These results were confirmed by poly-ADP ribose polymerase (PARP), an 85-kDa fragment resulting from PARP cleavage, where apicidin increased the level of PARP cleavage and caspase-3 activity in 1.0 microM apicidin-treated cells. Apicidin-induced apoptosis through caspase-3 activation was confirmed by the increase in the release of cytochrome c and the decrease in the Bax/Bcl-2 ratio. These results suggest that apicidin has anti-tumor properties on endometrial cancer cells by inducing selectively the genes related to cell cycle arrest and apoptosis.
Ahn
Mee Young
MY
College of Pharmacy, Pusan National University, San 30, Jangjeon-dong, Geumjung-gu, Busan 609-735, South Korea.
Lee
Jaewon
J
Na
Yong Jin
YJ
Choi
Wahn Soo
WS
Lee
Byung Mu
BM
Kang
Keon Wook
KW
Kim
Hyung Sik
HS
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis / Q000235:genetics; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D016889:Endometrial Neoplasms / Q000473:pathology*; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D010456:Peptides, Cyclic / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D006657:Histones; D010456:Peptides, Cyclic; D019253:Proto-Oncogene Proteins c-bcl-2; C102351:apicidin; D045304:Cytochromes c; D018844:Cyclin-Dependent Kinases; D053148:Caspase 3