Superior efficacy of co-treatment with dual PI3K/mTOR inhibitor NVP-BEZ235 and pan-histone deacetylase inhibitor against human pancreatic cancer
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Sreedhar Venkannagari1, Warren Fiskus1, Karissa Peth1, Peter Atadja2, Manuel Hidalgo3, Anirban Maitra4 and Kapil N. Bhalla1
1 The University of Kansas Cancer Center, Kansas City, KS,
2 Novartis Institute for Biomedical Research Inc., Cambridge, MA,
3 Centro Nacional de Investigaciones Oncologicas, C Melchor Fernandez Almagro 3, Madrid, Spain
4 The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD
Kapil N. Bhalla, email:
Keywords: Pancreatic cancer, pan-HDAC inhibitor, BEZ235, mTOR, AKT
Received: October 26, 2012, Accepted: November 13, 2012, Published: November 15, 2012
Genetic alterations activating K-RAS and PI3K/AKT signaling are also known to induce the activity of mTOR kinase through TORC1 and TORC2 complexes in human pancreatic ductal adenocarcinoma (PDAC). Here, we determined the effects of the dual PI3K and mTOR inhibitor, NVP-BEZ235 (BEZ235), and the pan-histone deacetylase inhibitor panobinostat (PS) against human PDAC cells. Treatment with BEZ235 or PS inhibited cell cycle progression with induction of the cell cycle inhibitory proteins, p21waf1 and p27kip1. BEZ235 and PS also dose dependently induced loss of cell viability of the cultured PDAC cells, associated with depletion of phosphorylated (p) AKT, as well as of the TORC1 substrates 4EBP1 and p70S6 kinase. While inhibiting p-AKT, treatment with PS induced the levels of the pro-apoptotic proteins BIM and BAK. Co-treatment with BEZ235 and PS synergistically induced apoptosis of the cultured PDAC cells. This was accompanied by marked attenuation of the levels of p-AKT and Bcl-xL but induction of BIM. Although in vivo treatment with BEZ235 or PS reduced tumor growth, co-treatment with BEZ235 and PS was significantly more effective in controlling the xenograft growth of Panc1 PDAC cells in the nude mice. Furthermore, co-treatment with BEZ235 and PS more effectively blocked tumor growth of primary PDAC heterotransplants (possessing K-RAS mutation and AKT2 amplification) subcutaneously implanted in the nude mice than each agent alone. These findings demonstrate superior activity and support further in vivo evaluation of combined treatment with BEZ235 and PS against PDAC that possess heightened activity of RAS-RAF-ERK1/2 and PI3K-AKT-mTOR pathways.
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