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Clinical Cancer Research Vol. 9, 1136-1144, March 2003
© 2003 American Association for Cancer Research

Experimental Therapeutics, Preclinical Pharmacology

The Proteasome Inhibitor PS-341 Markedly Enhances Sensitivity of Multiple Myeloma Tumor Cells to Chemotherapeutic Agents1

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 and James R. Berenson2

Division of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, California 90048 [M. H. M., H. H. Y., K. P., S. M., J. M. F., C. A., M. J. B., M. F., E. R., J. N., A. M., N. S-S., R. A. V., J. R. B.]; University of California Los Angeles School of Medicine and Jonsson Comprehensive Cancer Center, Los Angeles, California [M. H. M., H. H. Y., K. P., S. M., J. M. F., C. A., M. J. B., M. F., E. R., J. N., A. M., N. S-S., R. A. V., J. R. B.]; Division of Microbiology, University of California San Diego School of Medicine, San Diego, California [Z-q. W.]; and Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts [J. A.]

Increased nuclear factor {kappa}B (NF-{kappa}B) activity is associated with increased tumor cell survival in multiple myeloma. The function of NF-{kappa}B is inhibited through binding to its inhibitor, I{kappa}B. Release of activated NF-{kappa}B follows proteasome-mediated degradation of I{kappa}B resulting from phosphorylation of the inhibitor and, finally, conjugation with ubiquitin. We report that myeloma cells have enhanced I{kappa}B{alpha} phosphorylation and increased NF-{kappa}B activity compared with normal hematopoietic cells. The proteasome inhibitor PS-341 blocked nuclear translocation of NF-{kappa}B, blocked NF-{kappa}B 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 I{kappa}B{alpha}. Thus, these results suggest that inhibition of NF-{kappa}B with PS-341 may overcome chemoresistance and allow doses of chemotherapeutic agents to be markedly reduced with antitumor effects without significant toxicity.




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