The efficacy of a novel, dual PI3K/mTOR inhibitor NVP-BEZ235 to enhance chemotherapy and antiangiogenic response in pancreatic cancer

J Cell Biochem. 2012 Mar;113(3):784-91. doi: 10.1002/jcb.23405.

Abstract

Gemcitabine has limited clinical benefits for pancreatic ductal adenocarcinoma (PDAC). The phosphatidylinositol-3-kinase (PI3K)/AKT and mammalian target of rapamycin (mTOR) signaling pathways are frequently dysregulated in PDAC. We investigated the effects of NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, in combination with gemcitabine and endothelial monocyte activating polypeptide II (EMAP) in experimental PDAC. Cell proliferation and protein expression were analyzed by WST-1 assay and Western blotting. Animal survival experiments were performed in murine xenografts. BEZ235 caused a decrease in phospho-AKT and phospho-mTOR expression in PDAC (AsPC-1), endothelial (HUVECs), and fibroblast (WI-38) cells. BEZ235 inhibited in vitro proliferation of all four PDAC cell lines tested. Additive effects on proliferation inhibition were observed in the BEZ235-gemcitabine combination in PDAC cells and in combination of BEZ235 or EMAP with gemcitabine in HUVECs and WI-38 cells. BEZ235, alone or in combination with gemcitabine and EMAP, induced apoptosis in AsPC-1, HUVECs, and WI-38 cells as observed by increased expression of cleaved poly (ADP-ribose) polymerase-1 (PARP-1) and caspase-3 proteins. Compared to controls (median survival: 16 days), animal survival increased after BEZ235 and EMAP therapy alone (both 21 days) and gemcitabine monotherapy (28 days). Further increases in survival occurred in combination therapy groups BEZ235 + gemcitabine (30 days, P = 0.007), BEZ235 + EMAP (27 days, P = 0.02), gemcitabine + EMAP (31 days, P = 0.001), and BEZ235 + gemcitabine + EMAP (33 days, P = 0.004). BEZ235 has experimental PDAC antitumor activity in vitro and in vivo that is further enhanced by combination of gemcitabine and EMAP. These findings demonstrate advantages of combination therapy strategies targeting multiple pathways in pancreatic cancer treatment.

MeSH terms

  • Angiogenesis Inhibitors / administration & dosage
  • Angiogenesis Inhibitors / pharmacology
  • Angiogenesis Inhibitors / therapeutic use
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / enzymology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cytokines / administration & dosage
  • Cytokines / pharmacology
  • Cytokines / therapeutic use
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Deoxycytidine / therapeutic use
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Fibroblasts / drug effects
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Humans
  • Imidazoles / administration & dosage
  • Imidazoles / pharmacology*
  • Imidazoles / therapeutic use
  • Mice
  • Mice, SCID
  • Neoplasm Proteins / administration & dosage
  • Neoplasm Proteins / pharmacology
  • Neoplasm Proteins / therapeutic use
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / enzymology
  • Phosphoinositide-3 Kinase Inhibitors*
  • Quinolines / administration & dosage
  • Quinolines / pharmacology*
  • Quinolines / therapeutic use
  • RNA-Binding Proteins / administration & dosage
  • RNA-Binding Proteins / pharmacology
  • RNA-Binding Proteins / therapeutic use
  • Signal Transduction / drug effects
  • Survival Analysis
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*

Substances

  • Angiogenesis Inhibitors
  • Cytokines
  • Enzyme Inhibitors
  • Imidazoles
  • Neoplasm Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Quinolines
  • RNA-Binding Proteins
  • small inducible cytokine subfamily E, member 1
  • Deoxycytidine
  • gemcitabine
  • TOR Serine-Threonine Kinases
  • dactolisib