The dual PI3K/mTOR inhibitor NVP-BGT226 induces cell cycle arrest and regulates Survivin gene expression in human pancreatic cancer cell lines

• Published in: Tumor biology 2012-06, Vol.33 (3), p.757-765
• Main Authors: Glienke, Wolfgang, Maute, Luise, Wicht, Johannes, Bergmann, Lothar
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Apoptosis - genetics; bcl-X Protein - genetics; bcl-X Protein - metabolism; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell Survival - drug effects; Cellular biology; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Humans; Imidazoles - pharmacology; Inhibitor drugs; Inhibitor of Apoptosis Proteins - genetics; Inhibitor of Apoptosis Proteins - metabolism; Myeloid Cell Leukemia Sequence 1 Protein; Pancreatic cancer; Pancreatic Neoplasms - enzymology; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-bcl-2 - genetics; Quinolines - pharmacology; Research Article; RNA, Small Interfering - metabolism; TOR Serine-Threonine Kinases - antagonists & inhibitors
• ISSN: 1010-4283; 1423-0380
• DOI: 10.1007/s13277-011-0290-2

The phosphatidylinositol-3-kinase (PI3K) pathway is one of the most commonly activated signaling pathways in pancreatic cancer and is a target of interest for new therapeutic approaches. NVP-BGT226 is a novel dual class PI3K/mammalian target of rapamycin (mTOR) inhibitor that has entered Phase I/II clinical trials. We analyzed the effect of NVP-BGT226 (10–100 nM) on the pancreatic cell lines Panc-1, BxPc-3, AsPC-1 and MiaPaCa-2 in regard to cell viability, induction of apoptosis, cell cycle, and expression of the antiapoptotic genes Survivin , MCL-1 , BCL-2 and BCL-xL . Cell viability decreased within 24–72 h after exposure to about 50% compared to untreated control cells in a concentration- but not time-dependent manner. Cell cycle analysis revealed that NVP-BGT226 induced predominantly G0/G1 cell cycle arrest. Additionally, real-time RT-PCR and Western blot analysis showed a remarkable decrease of Survivin expression. Originally designed as a dual inhibitor, there was only a significant inhibition of p-mTOR. In summary, the dual PI3K/mTOR inhibitor NVP-BGT226 induces G0/G1 arrest and acts, at least, partially via downregulation of Survivin.