Combination effects of bortezomib with gemcitabine and EMAP II in experimental pancreatic cancer

Niranjan Awasthi, Margaret Schwarz, Roderich E. Schwarz

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The proteasome inhibitor bortezomib (B) has been shown to enhance gemcitabine (G) effects against pancreatic ductal adenocarcinoma (PDAC). endothelial monocyte activating polypeptide II (EMAP, E) is an antiendothelial and antiangiogenic cytokine. We tested the combination effects of bortezomib, gemcitabine and EMAP in experimental PDAC. Bortezomib inhibited the in vitro proliferation of PDAC and endothelial cells, with additive effects in combination with gemcitabine or EMAP. Bortezomib induced apoptosis as observed by PARP-1 cleavage; it also increased the expression of p21 (>27-fold) and p27 (>2.5-fold), with additive effects in combination with gemcitabine and EMAP. Bortezomib caused a decrease in the expression of the antiapoptotic protein Bcl-2, and an increase in the proapoptotic protein Bax and in p53. Bortezomib had no effect on the intracellular levels of full length or mature EMAP. an in vivo murine xenograft model showed extended survival in all combination groups except B + E compared with control or monotherapy, but no benefit of B + E + G over E + G. The relative local tumor growth compared to controls after bortezomib, EMAP, gemcitabine, B + G, E + G or B + E + G was 92%, 52%, 48%, 36%, 18% and 35%, respectively. Our results show that in vitro bortezomib had an antiproliferative and proapoptotic effect, and it's combination with gemcitabine and EMAP increased these effects. In vivo, bortezomib had no anti-tumor effect by itself, enhanced gemcitabine effects in combination, but failed to further significantly improve the E + G combination benefit. The potential value of proteasome inhibition in experimental therapy approaches for PDAC appears to relate primarily to the combination with the cytotoxic drug rather than with the antiendothelial agent.

Original languageEnglish (US)
Pages (from-to)99-107
Number of pages9
JournalCancer Biology and Therapy
Volume10
Issue number1
StatePublished - Jul 1 2010
Externally publishedYes

Fingerprint

gemcitabine
Pancreatic Neoplasms
Adenocarcinoma
Bortezomib
small inducible cytokine subfamily E, member 1
bcl-2-Associated X Protein
Investigational Therapies
Proteasome Inhibitors
Proteasome Endopeptidase Complex
Heterografts

Keywords

  • Bortezomib
  • Combination therapy
  • EMAP II
  • Pancreatic cancer
  • Proteasome inhibition

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Molecular Medicine
  • Pharmacology

Cite this

Combination effects of bortezomib with gemcitabine and EMAP II in experimental pancreatic cancer. / Awasthi, Niranjan; Schwarz, Margaret; Schwarz, Roderich E.

In: Cancer Biology and Therapy, Vol. 10, No. 1, 01.07.2010, p. 99-107.

Research output: Contribution to journalArticle

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abstract = "The proteasome inhibitor bortezomib (B) has been shown to enhance gemcitabine (G) effects against pancreatic ductal adenocarcinoma (PDAC). endothelial monocyte activating polypeptide II (EMAP, E) is an antiendothelial and antiangiogenic cytokine. We tested the combination effects of bortezomib, gemcitabine and EMAP in experimental PDAC. Bortezomib inhibited the in vitro proliferation of PDAC and endothelial cells, with additive effects in combination with gemcitabine or EMAP. Bortezomib induced apoptosis as observed by PARP-1 cleavage; it also increased the expression of p21 (>27-fold) and p27 (>2.5-fold), with additive effects in combination with gemcitabine and EMAP. Bortezomib caused a decrease in the expression of the antiapoptotic protein Bcl-2, and an increase in the proapoptotic protein Bax and in p53. Bortezomib had no effect on the intracellular levels of full length or mature EMAP. an in vivo murine xenograft model showed extended survival in all combination groups except B + E compared with control or monotherapy, but no benefit of B + E + G over E + G. The relative local tumor growth compared to controls after bortezomib, EMAP, gemcitabine, B + G, E + G or B + E + G was 92{\%}, 52{\%}, 48{\%}, 36{\%}, 18{\%} and 35{\%}, respectively. Our results show that in vitro bortezomib had an antiproliferative and proapoptotic effect, and it's combination with gemcitabine and EMAP increased these effects. In vivo, bortezomib had no anti-tumor effect by itself, enhanced gemcitabine effects in combination, but failed to further significantly improve the E + G combination benefit. The potential value of proteasome inhibition in experimental therapy approaches for PDAC appears to relate primarily to the combination with the cytotoxic drug rather than with the antiendothelial agent.",
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