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KMID : 1137020080190010026
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Journal of Gynecologic Oncology
2008 Volume.19 No. 1 p.26 ~ p.39
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Induction of apoptosis by the kinase inhibitor flavopiridol in human ovarian cancer cell Lines
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Hur Soo-Young
Lee Jun-Mo
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Abstract
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Objective : Flavopiridol that inhibits cyclin-dependent kinase, can cause cell cycle arrest, induce apoptosis in human tumor cell lines. In the present study, we investigated apoptotic effects of flavopiridol and the underlying molecular
mechanisms in human ovarian cancer cell lines.
Methods : We used TOV-21G and TOV-112D cell lines. The cell viability was tested by MTT assay and apoptosis was assessed by TUNEL assay and annexin-V binding. Western blot was used to examine apoptosis related protein levels. MAP kinase activity was analyzed by non-radioactive MAP kinase assay kit.
Results : Treatment of TOV-21G and TOV-112D cells with flavopiridol (50 nM to 1000 nM) led to a dose- and
time-dependent inhibition of cell growth and survival. Dose-related induction of apoptosis was also observed in these
cell lines. Flavopiridol (500 nM) induced striking decreases in the levels of the antiapoptic proteins Mcl-1, Bcl-XL, and
XIAP in both cell lines. In contrast, expression of Bax, Bcl-2, and AIF was not significantly influenced by flavopiridol.
Although flavopiridol resulted in accumulation of p53 in both cells, flavopiridol mediated apoptosis was p53 independent
because it occurred to the same degree in TOV-112D cells in which p53 was inactivated by mutation. Flavopiridol treatment resulted in enhanced cleavage of pro-caspase 9 and activation of caspase 3. Apoptosis was associated with suppression of ERK activity.
Conclusion : Although the precise mechanisms of flavopiridol mediated cytotoxicity have not been fully defined, these data suggest that flavopiridol has activity against ovarian cancers in vitro and is worthy of continued clinical development in the treatment of ovarian cancer.
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KEYWORD
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Flavopiridol, Ovarian cancer cell lines, Apoptosis
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