The effect of dual PI3K/mTOR inhibitor NVP-BGT226 on cell cycle and survivin and STAT3 gene expression in human pancreatic cancer cell lines.

Abstract

e14523 Background: The phosphatidylinositol-3-kinase (PI3K) pathway is one of the most commonly activated signaling pathways in pancreatic cancer. The inhibition of this transducing pathway may open new options for the treatment of pancreatic cancer. NVP-BGT226 is a novel dual class PI3K/mammalian target of rapamycin (mTOR) inhibitor that has entered Phase I/II clinical trials. Methods: We have tested the effects of NVP-BGT226 on cell viability (M'TT assay), apoptosis (AnnexinV/PI-FACS and PARP1 cleavage), cell cycle (FACS PI/RNAse-staining) and expression of Survivin, STAT3 and BCL-xL with Real-time RT-PCR and Western blot in the human pancreatic cancer cell lines Panc-1, BxPc-3, AsPC-1 and MiaPaCa-2. Results: The cell viability decreased within 24-72 hours exposure to about 50% compared to untreated control cells in a concentration and but not time dependent manner. Apoptosis was not detected, but cell cycle analysis revealed that NVP-BGT226 induced predominantly a G0/G1-arrest to about 90-95%. Analysis with Real-time RT-PCR and Western blot showed a remarkable reduction of Survivin and STAT3 expression but an increase of the anti-apoptotic BCL-xL gene expression. Conclusions: The PI3K/mTOR inhibitor NVP-BGT226 induces G0/G1-arrest and and acts via downregulation of Survivin and STAT3.