Proteasome inhibition enhances antitumour effects of gemcitabine in experimental pancreatic cancer

Niranjan Awasthi, Margaret Schwarz, Roderich E. Schwarz

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Background: The clinical benefit of gemcitabine, the standard systemic therapy of pancreatic cancer (PaCa), remains modest as a result of high chemoresistance. The proteasome inhibitor bortezomib has antitumour activity against PaCa in vitro and in vivo. We examined the antitumour activity of combination PaCa therapy with bortezomib and gemcitabine. Methods: Cell proliferation assays were performed using WST-1 reagent. Protein expression was determined by Western blotting. Efficacy of bortezomib and/or gemcitabine was tested in vivo in a survival study. Results: Bortezomib at 10 μM caused 29% and 72% inhibition in AsPC-1 PaCa cell proliferation at 48 and 96 h incubation, respectively. Bortezomib was even more active against PaCa cell lines Panc-1 and MiaPaCa, with 80% inhibition of proliferation at 48 h. The combination of bortezomib and gemcitabine inhibited AsPC-1 proliferation more effectively compared with each single agent alone. Poly(ADP-ribose) polymerase (PARP) cleavage, an apoptotic indicator, reached 6.6-, 2- and 8.5-fold over controls for bortezomib, gemcitabine and the combination. The median survival was 31 (controls and bortezomib), 40 (gemcitabine) and 48 days (combination), respectively (P <0.002). Conclusions: Bortezomib and gemcitabine demonstrate additive antitumour activity in vitro and in an experimental PaCa model, indicating the potential for clinical PaCa benefits of additional multiagent therapies that will be based upon the bortezomib and gemcitabine combination.

Original languageEnglish (US)
Pages (from-to)600-605
Number of pages6
JournalHPB
Volume11
Issue number7
DOIs
StatePublished - 2009
Externally publishedYes

Fingerprint

gemcitabine
Proteasome Endopeptidase Complex
Pancreatic Neoplasms
Cell Proliferation
Bortezomib
Proteasome Inhibitors
Poly(ADP-ribose) Polymerases

Keywords

  • Bortezomib combination therapy
  • Experimental therapy
  • Pancreatic cancer
  • Proteasome inhibition

ASJC Scopus subject areas

  • Gastroenterology
  • Hepatology

Cite this

Proteasome inhibition enhances antitumour effects of gemcitabine in experimental pancreatic cancer. / Awasthi, Niranjan; Schwarz, Margaret; Schwarz, Roderich E.

In: HPB, Vol. 11, No. 7, 2009, p. 600-605.

Research output: Contribution to journalArticle

Awasthi, Niranjan ; Schwarz, Margaret ; Schwarz, Roderich E. / Proteasome inhibition enhances antitumour effects of gemcitabine in experimental pancreatic cancer. In: HPB. 2009 ; Vol. 11, No. 7. pp. 600-605.
@article{eb18ceb4619c4de6a9463d047157b1a2,
title = "Proteasome inhibition enhances antitumour effects of gemcitabine in experimental pancreatic cancer",
abstract = "Background: The clinical benefit of gemcitabine, the standard systemic therapy of pancreatic cancer (PaCa), remains modest as a result of high chemoresistance. The proteasome inhibitor bortezomib has antitumour activity against PaCa in vitro and in vivo. We examined the antitumour activity of combination PaCa therapy with bortezomib and gemcitabine. Methods: Cell proliferation assays were performed using WST-1 reagent. Protein expression was determined by Western blotting. Efficacy of bortezomib and/or gemcitabine was tested in vivo in a survival study. Results: Bortezomib at 10 μM caused 29{\%} and 72{\%} inhibition in AsPC-1 PaCa cell proliferation at 48 and 96 h incubation, respectively. Bortezomib was even more active against PaCa cell lines Panc-1 and MiaPaCa, with 80{\%} inhibition of proliferation at 48 h. The combination of bortezomib and gemcitabine inhibited AsPC-1 proliferation more effectively compared with each single agent alone. Poly(ADP-ribose) polymerase (PARP) cleavage, an apoptotic indicator, reached 6.6-, 2- and 8.5-fold over controls for bortezomib, gemcitabine and the combination. The median survival was 31 (controls and bortezomib), 40 (gemcitabine) and 48 days (combination), respectively (P <0.002). Conclusions: Bortezomib and gemcitabine demonstrate additive antitumour activity in vitro and in an experimental PaCa model, indicating the potential for clinical PaCa benefits of additional multiagent therapies that will be based upon the bortezomib and gemcitabine combination.",
keywords = "Bortezomib combination therapy, Experimental therapy, Pancreatic cancer, Proteasome inhibition",
author = "Niranjan Awasthi and Margaret Schwarz and Schwarz, {Roderich E.}",
year = "2009",
doi = "10.1111/j.1477-2574.2009.00109.x",
language = "English (US)",
volume = "11",
pages = "600--605",
journal = "HPB",
issn = "1365-182X",
publisher = "John Wiley and Sons Inc.",
number = "7",

}

TY - JOUR

T1 - Proteasome inhibition enhances antitumour effects of gemcitabine in experimental pancreatic cancer

AU - Awasthi, Niranjan

AU - Schwarz, Margaret

AU - Schwarz, Roderich E.

PY - 2009

Y1 - 2009

N2 - Background: The clinical benefit of gemcitabine, the standard systemic therapy of pancreatic cancer (PaCa), remains modest as a result of high chemoresistance. The proteasome inhibitor bortezomib has antitumour activity against PaCa in vitro and in vivo. We examined the antitumour activity of combination PaCa therapy with bortezomib and gemcitabine. Methods: Cell proliferation assays were performed using WST-1 reagent. Protein expression was determined by Western blotting. Efficacy of bortezomib and/or gemcitabine was tested in vivo in a survival study. Results: Bortezomib at 10 μM caused 29% and 72% inhibition in AsPC-1 PaCa cell proliferation at 48 and 96 h incubation, respectively. Bortezomib was even more active against PaCa cell lines Panc-1 and MiaPaCa, with 80% inhibition of proliferation at 48 h. The combination of bortezomib and gemcitabine inhibited AsPC-1 proliferation more effectively compared with each single agent alone. Poly(ADP-ribose) polymerase (PARP) cleavage, an apoptotic indicator, reached 6.6-, 2- and 8.5-fold over controls for bortezomib, gemcitabine and the combination. The median survival was 31 (controls and bortezomib), 40 (gemcitabine) and 48 days (combination), respectively (P <0.002). Conclusions: Bortezomib and gemcitabine demonstrate additive antitumour activity in vitro and in an experimental PaCa model, indicating the potential for clinical PaCa benefits of additional multiagent therapies that will be based upon the bortezomib and gemcitabine combination.

AB - Background: The clinical benefit of gemcitabine, the standard systemic therapy of pancreatic cancer (PaCa), remains modest as a result of high chemoresistance. The proteasome inhibitor bortezomib has antitumour activity against PaCa in vitro and in vivo. We examined the antitumour activity of combination PaCa therapy with bortezomib and gemcitabine. Methods: Cell proliferation assays were performed using WST-1 reagent. Protein expression was determined by Western blotting. Efficacy of bortezomib and/or gemcitabine was tested in vivo in a survival study. Results: Bortezomib at 10 μM caused 29% and 72% inhibition in AsPC-1 PaCa cell proliferation at 48 and 96 h incubation, respectively. Bortezomib was even more active against PaCa cell lines Panc-1 and MiaPaCa, with 80% inhibition of proliferation at 48 h. The combination of bortezomib and gemcitabine inhibited AsPC-1 proliferation more effectively compared with each single agent alone. Poly(ADP-ribose) polymerase (PARP) cleavage, an apoptotic indicator, reached 6.6-, 2- and 8.5-fold over controls for bortezomib, gemcitabine and the combination. The median survival was 31 (controls and bortezomib), 40 (gemcitabine) and 48 days (combination), respectively (P <0.002). Conclusions: Bortezomib and gemcitabine demonstrate additive antitumour activity in vitro and in an experimental PaCa model, indicating the potential for clinical PaCa benefits of additional multiagent therapies that will be based upon the bortezomib and gemcitabine combination.

KW - Bortezomib combination therapy

KW - Experimental therapy

KW - Pancreatic cancer

KW - Proteasome inhibition

UR - http://www.scopus.com/inward/record.url?scp=73349129983&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=73349129983&partnerID=8YFLogxK

U2 - 10.1111/j.1477-2574.2009.00109.x

DO - 10.1111/j.1477-2574.2009.00109.x

M3 - Article

VL - 11

SP - 600

EP - 605

JO - HPB

JF - HPB

SN - 1365-182X

IS - 7

ER -