Effects of the proteasome inhibitor ps-341 on apoptosis and angiogenesis in orthotopic human pancreatic tumor xenografts

Steffan T. Nawrocki, Christiane J. Bruns, Matthew T. Harbison, Richard J. Bold, Bridget Sweeney Gotsch, James L. Abbruzzese, Peter Elliott, Julian Adams, David J. McConkey

Research output: Contribution to journalArticlepeer-review

150 Scopus citations

Abstract

Recent studies have shown that the transcription factor, nuclear factor κB (NF-κB), regulates critical survival pathways in a variety of different cell types, including human pancreatic cancer cells. The activation of NF-κB is controlled by proteasome-mediated degradation of its endogenous polypeptide inhibitor, inhibitor of nuclear factor κBα. We investigated the effects of PS-341, a peptide boronate inhibitor of the proteasome in human pancreatic cancer cells in vitro and in vivo. Comparison of PS-341's effects on the growth of eight different human pancreatic cancer cell lines revealed marked heterogeneity in drug responsiveness, ranging from highly resistant (IC50 > 10 μM; Panc-48, HS766T, and Mia-PaCa-2) to extremely sensitive (IC50 < 40 nM; L3.6pl, Hpaf2, and BxPC3). However, these effects did not correlate with differential inhibition of NF-κB activation. Direct quantification of apoptosis revealed that PS-341's effects on cell growth largely correlated with sensitivity to programmed cell death. Evaluation of PS-341's effects on established orthotopic tumor xenografts demonstrated that biweekly intravenous administration of the maximum-tolerated dose of the drug (1 mg/kg) led to significant reductions in the volumes of L3.6pl tumors but not Mia-PaCa-2 tumors. Laser scanning cytometer-mediated quantification of drug-induced apoptosis in the xenografts confirmed that PS-341 induced DNA fragmentation and activation of caspase-3 in L3.6pl tumors but not in Mia-PaCa-2 tumors. However, histological examination of drug-treated tumors revealed extensive central necrosis and reductions in microvessel density and VEGF expression in both tumor types. Taken together, our results demonstrate that PS-341 inhibits the growth of human pancreatic tumors via direct effects on tumor cells and indirect effects on the tumor vasculature.

Original languageEnglish (US)
Pages (from-to)1243-1253
Number of pages11
JournalMolecular cancer therapeutics
Volume1
Issue number14
StatePublished - Dec 1 2002

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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