PMID- 22020918
OWN - NLM
STAT- MEDLINE
DCOM- 20120629
LR  - 20221207
IS  - 1097-4644 (Electronic)
IS  - 0730-2312 (Linking)
VI  - 113
IP  - 3
DP  - 2012 Mar
TI  - The efficacy of a novel, dual PI3K/mTOR inhibitor NVP-BEZ235 to enhance 
      chemotherapy and antiangiogenic response in pancreatic cancer.
PG  - 784-91
LID - 10.1002/jcb.23405 [doi]
AB  - 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.
CI  - Copyright (c) 2011 Wiley Periodicals, Inc.
FAU - Awasthi, Niranjan
AU  - Awasthi N
AD  - Division of Surgical Oncology, Department of Surgery, The University of Texas 
      Southwestern Medical Center, Dallas, Texas 75390, USA.
FAU - Yen, Peter L
AU  - Yen PL
FAU - Schwarz, Margaret A
AU  - Schwarz MA
FAU - Schwarz, Roderich E
AU  - Schwarz RE
LA  - eng
PT  - Journal Article
PL  - United States
TA  - J Cell Biochem
JT  - Journal of cellular biochemistry
JID - 8205768
RN  - 0 (Angiogenesis Inhibitors)
RN  - 0 (Cytokines)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Imidazoles)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Quinolines)
RN  - 0 (RNA-Binding Proteins)
RN  - 0 (small inducible cytokine subfamily E, member 1)
RN  - 0W860991D6 (Deoxycytidine)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - RUJ6Z9Y0DT (dactolisib)
RN  - 0 (Gemcitabine)
SB  - IM
MH  - Angiogenesis Inhibitors/administration & dosage/pharmacology/therapeutic use
MH  - Animals
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology/therapeutic use
MH  - Carcinoma, Pancreatic Ductal/*drug therapy/enzymology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cytokines/administration & dosage/pharmacology/therapeutic use
MH  - Deoxycytidine/administration & dosage/analogs & 
      derivatives/pharmacology/therapeutic use
MH  - Enzyme Inhibitors/administration & dosage/pharmacology/therapeutic use
MH  - Female
MH  - Fibroblasts/drug effects
MH  - Human Umbilical Vein Endothelial Cells/drug effects
MH  - Humans
MH  - Imidazoles/administration & dosage/*pharmacology/therapeutic use
MH  - Mice
MH  - Mice, SCID
MH  - Neoplasm Proteins/administration & dosage/pharmacology/therapeutic use
MH  - Pancreatic Neoplasms/*drug therapy/enzymology
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Quinolines/administration & dosage/*pharmacology/therapeutic use
MH  - RNA-Binding Proteins/administration & dosage/pharmacology/therapeutic use
MH  - Signal Transduction/drug effects
MH  - Survival Analysis
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Gemcitabine
EDAT- 2011/10/25 06:00
MHDA- 2012/06/30 06:00
CRDT- 2011/10/25 06:00
PHST- 2011/10/25 06:00 [entrez]
PHST- 2011/10/25 06:00 [pubmed]
PHST- 2012/06/30 06:00 [medline]
AID - 10.1002/jcb.23405 [doi]
PST - ppublish
SO  - J Cell Biochem. 2012 Mar;113(3):784-91. doi: 10.1002/jcb.23405.