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

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Tumor Biology

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.

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Acknowledgements

This work was supported by the Detlef Hübner Stiftung, Hochheim; Alfons und Gertrud Kassel-Stiftung, Frankfurt am Main; Senckenbergische-Stiftung, Frankfurt am Main, Tumorzentrum Rhein-Main e. V. and the Research Support Foundation, Vaduz/Liechtenstein.

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No potential conflicts of interest were disclosed.

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Authors and Affiliations

  1. Medical Clinic II (Hematology/Oncology), University Hospital, J.W. Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany

    Wolfgang Glienke, Luise Maute, Johannes Wicht & Lothar Bergmann

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  1. Wolfgang Glienke
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  2. Luise Maute
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  3. Johannes Wicht
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  4. Lothar Bergmann
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Correspondence to Lothar Bergmann.

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Glienke, W., Maute, L., Wicht, J. et al. The dual PI3K/mTOR inhibitor NVP-BGT226 induces cell cycle arrest and regulates Survivin gene expression in human pancreatic cancer cell lines. Tumor Biol. 33, 757–765 (2012). https://doi.org/10.1007/s13277-011-0290-2

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  • DOI: https://doi.org/10.1007/s13277-011-0290-2

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