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

Niranjan Awasthi, Peter L. Yen, Margaret Schwarz, Roderich E. Schwarz

Research output: Contribution to journalArticle

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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 NVPBEZ235, 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, P1/40.007), BEZ235+EMAP (27 days, P1/40.02), gemcitabine+EMAP (31 days, P1/40.001), and BEZ235+gemcitabine+EMAP (33 days, P1/40.004). 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.

Original languageEnglish (US)
Pages (from-to)784-791
Number of pages8
JournalJournal of Cellular Biochemistry
Volume113
Issue number3
DOIs
StatePublished - Mar 2012
Externally publishedYes

Fingerprint

gemcitabine
Phosphatidylinositol 3-Kinase
Chemotherapy
Sirolimus
Pancreatic Neoplasms
Drug Therapy
Adenocarcinoma
Animals
dactolisib
Oncology
Poly(ADP-ribose) Polymerases
small inducible cytokine subfamily E, member 1
Cell proliferation
Fibroblasts
Group Psychotherapy

Keywords

  • Combination Therapy
  • Gemcitabine
  • Nvp-Bez235
  • Pancreatic Cancer

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

The efficacy of a novel, dual PI3K/mTOR inhibitor NVP-BEZ235 to enhance chemotherapy and antiangiogenic response in pancreatic cancer. / Awasthi, Niranjan; Yen, Peter L.; Schwarz, Margaret; Schwarz, Roderich E.

In: Journal of Cellular Biochemistry, Vol. 113, No. 3, 03.2012, p. 784-791.

Research output: Contribution to journalArticle

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N2 - 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 NVPBEZ235, 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, P1/40.007), BEZ235+EMAP (27 days, P1/40.02), gemcitabine+EMAP (31 days, P1/40.001), and BEZ235+gemcitabine+EMAP (33 days, P1/40.004). 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.

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 NVPBEZ235, 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, P1/40.007), BEZ235+EMAP (27 days, P1/40.02), gemcitabine+EMAP (31 days, P1/40.001), and BEZ235+gemcitabine+EMAP (33 days, P1/40.004). 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.

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