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 2002
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Drug Discovery
  • Pharmacology

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