The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents

Mark H. Ma, Hank H. Yang, Kimberly Parker, Steven Manyak, Jeffrey M. Friedman, Cibby Altamirano, Zhi qun Wu, Mitesh J. Borad, Malka Frantzen, Evanthia Roussos, Jason Neeser, Amy Mikail, Julian Adams, Nelida Sjak-Shie, Robert A. Vescio, James R. Berenson

Research output: Contribution to journalArticlepeer-review

376 Scopus citations

Abstract

Increased nuclear factor κB (NF-κB) activity is associated with increased tumor cell survival in multiple myeloma. The function of NF-κB is inhibited through binding to its inhibitor, IκB. Release of activated NF-κB follows proteasome-mediated degradation of IκB resulting from phosphorylation of the inhibitor and, finally, conjugation with ubiquitin. We report that myeloma cells have enhanced IκBα phosphorylation and increased NF-κB activity compared with normal hematopoietic cells. The proteasome inhibitor PS-341 blocked nuclear translocation of NF-κB, blocked NF-κB DNA binding, and demonstrated consistent antitumor activity against chemoresistant and chemosensitive myeloma cells. The sensitivity of chemoresistant myeloma cells to chemotherapeutic agents was markedly increased (100,000-1,000,000-fold) when combined with a noncytotoxic dose of PS-341 without affecting normal hematopoietic cells. Similar effects were observed using a dominant negative super-repressor for IκBα. Thus, these results suggest that inhibition of NF-κB with PS-341 may overcome chemoresistance and allow doses of chemotherapeutic agents to be markedly reduced with antitumor effects without significant toxicity.

Original languageEnglish (US)
Pages (from-to)1136-1144
Number of pages9
JournalClinical Cancer Research
Volume9
Issue number3
StatePublished - Mar 1 2003

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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