Smac mimetic increases chemotherapy response and improves survival in mice with pancreatic cancer

Sean P. Dineen, Christina L. Roland, Rachel Greer, Juliet G. Carbon, Jason E. Toombs, Puja Gupta, Nabeel Bardeesy, Haizhou Sun, Noelle Williams, John D. Minna, Rolf A. Brekken

Research output: Contribution to journalArticle

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Abstract

Failure of chemotherapy in the treatment of pancreatic cancer is often due to resistance to therapy-induced apoptosis. A major mechanism for such resistance is the expression and activity of inhibitors of apoptosis proteins (IAP). Smac (second mitochondria-derived activator of caspase) is a mitochondrial protein that inhibits IAPs. We show that JP1201, a Smac mimetic, is a potent enhancer of chemotherapy in robust mouse models of pancreatic cancer. Combination of JP1201 with gemcitabine reduced primary and metastatic tumor burden in orthotopic xenograft and syngenic tumor models, induced regression of established tumors, and prolonged survival in xenograft and transgenic models of pancreatic cancer. The effect of JP1201 was phenocopied by XIAP small interfering RNA in vitro and correlated with elevated levels of tumor necrosis factor a protein in vivo. The continued development of JP1201 and other strategies designed to enhance therapy-induced apoptosis in pancreatic cancer is warranted.

Original languageEnglish (US)
Pages (from-to)2852-2861
Number of pages10
JournalCancer Research
Volume70
Issue number7
DOIs
StatePublished - Apr 1 2010

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Caspases
Pancreatic Neoplasms
Mitochondria
Drug Therapy
gemcitabine
Heterografts
Apoptosis
Inhibitor of Apoptosis Proteins
Mitochondrial Proteins
Tumor Burden
Small Interfering RNA
Neoplasms
Therapeutics
Tumor Necrosis Factor-alpha
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Smac mimetic increases chemotherapy response and improves survival in mice with pancreatic cancer. / Dineen, Sean P.; Roland, Christina L.; Greer, Rachel; Carbon, Juliet G.; Toombs, Jason E.; Gupta, Puja; Bardeesy, Nabeel; Sun, Haizhou; Williams, Noelle; Minna, John D.; Brekken, Rolf A.

In: Cancer Research, Vol. 70, No. 7, 01.04.2010, p. 2852-2861.

Research output: Contribution to journalArticle

Dineen, SP, Roland, CL, Greer, R, Carbon, JG, Toombs, JE, Gupta, P, Bardeesy, N, Sun, H, Williams, N, Minna, JD & Brekken, RA 2010, 'Smac mimetic increases chemotherapy response and improves survival in mice with pancreatic cancer', Cancer Research, vol. 70, no. 7, pp. 2852-2861. https://doi.org/10.1158/0008-5472.CAN-09-3892
Dineen, Sean P. ; Roland, Christina L. ; Greer, Rachel ; Carbon, Juliet G. ; Toombs, Jason E. ; Gupta, Puja ; Bardeesy, Nabeel ; Sun, Haizhou ; Williams, Noelle ; Minna, John D. ; Brekken, Rolf A. / Smac mimetic increases chemotherapy response and improves survival in mice with pancreatic cancer. In: Cancer Research. 2010 ; Vol. 70, No. 7. pp. 2852-2861.
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