Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Apoptosis / genetics
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Cell Cycle Checkpoints / drug effects*
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Cell Line, Tumor
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Cell Survival / drug effects
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Imidazoles / pharmacology*
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Inhibitor of Apoptosis Proteins / genetics*
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Inhibitor of Apoptosis Proteins / metabolism
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Myeloid Cell Leukemia Sequence 1 Protein
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Pancreatic Neoplasms / enzymology
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Pancreatic Neoplasms / genetics*
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Pancreatic Neoplasms / metabolism
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Phosphoinositide-3 Kinase Inhibitors*
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Quinolines / pharmacology*
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RNA, Small Interfering / metabolism
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Survivin
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TOR Serine-Threonine Kinases / antagonists & inhibitors*
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bcl-X Protein / genetics
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bcl-X Protein / metabolism
Substances
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8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl)-1,3-dihydroimidazo(4,5-c)quinolin-2-one
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Antineoplastic Agents
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BIRC5 protein, human
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Imidazoles
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Inhibitor of Apoptosis Proteins
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Myeloid Cell Leukemia Sequence 1 Protein
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins c-bcl-2
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Quinolines
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RNA, Small Interfering
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Survivin
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bcl-X Protein
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases