An exogenous cdk inhibitor, butyrolactone-I, induces apoptosis with increased Bax/Bcl-2 ratio in p53-mutated pancreatic cancer cells

We investigated the effects of an exogenous cdk inhibitor, butyrolactone-I, on cell growth inhibition, apoptosis induction, and the regulation of apoptosis in pancreatic cancer cells with mutated p53. Cell growth was dose-dependently inhibited by Butyrolactone-I in PANC-1 and AsPC-1 cells. Phosphorylation of pRb and Cyclin A expression were significantly inhibited in Butyrolactone-I-treated cells. Apoptotic cell death was detected by both Hoechst staining and TUNEL assay. In butyrolactone-I-treated PANC-1 cells, expression of p53 protein was unchanged, but Bax expression was slightly up-regulated and Bcl-2 expression was predominantly down-regulated. Bax/Bcl-2 ratio reached 9.6-fold increase compared to the control at the maximum. The time course of changes in Bax/Bcl-2 ratio was similar to that in the TUNEL-positive ratio. These data, suggest that dynamic changes of the Bax/Bcl-2 ratio might be important in determining point of apoptosis induction in pancreatic cancer cells with p53 mutation.