The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents.
Increased nuclear factor kappaB (NF-kappaB) activity is associated with increased tumor cell survival in multiple myeloma. The function of NF-kappaB is inhibited through binding to its inhibitor, IkappaB. Release of activated NF-kappaB follows proteasome-mediated degradation of IkappaB resulting from phosphorylation of the inhibitor and, finally, conjugation with ubiquitin. We report that myeloma cells have enhanced IkappaBalpha phosphorylation and increased NF-kappaB activity compared with normal hematopoietic cells. The proteasome inhibitor PS-341 blocked nuclear translocation of NF-kappaB, blocked NF-kappaB 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 IkappaBalpha. Thus, these results suggest that inhibition of NF-kappaB with PS-341 may overcome chemoresistance and allow doses of chemotherapeutic agents to be markedly reduced with antitumor effects without significant toxicity.
Ma
Mark H
MH
Division of Hematology and Oncology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
Yang
Hank H
HH
Parker
Kimberly
K
Manyak
Steven
S
Friedman
Jeffrey M
JM
Altamirano
Cibby
C
Wu
Zhi-qun
ZQ
Borad
Mitesh J
MJ
Frantzen
Malka
M
Roussos
Evanthia
E
Neeser
Jason
J
Mikail
Amy
A
Adams
Julian
J
Sjak-Shie
Nelida
N
Vescio
Robert A
RA
Berenson
James R
JR
D021581:Active Transport, Cell Nucleus; D000256:Adenoviridae / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D003546:Cysteine Endopeptidases; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005799:Genes, Dominant; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008558:Melphalan / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D009101:Multiple Myeloma / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D011719:Pyrazines / Q000494:pharmacology*; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism
D000970:Antineoplastic Agents; D001897:Boronic Acids; D020672:I-kappa B Proteins; D009097:Multienzyme Complexes; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011719:Pyrazines; D013778:Tetrazolium Salts; D013844:Thiazoles; D025801:Ubiquitin; D000072000:NF-KappaB Inhibitor alpha; D000069286:Bortezomib; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C022616:thiazolyl blue; D008558:Melphalan