The role of nuclear factor-kappaB in the biology and treatment of multiple myeloma.
Increased nuclear factor (NF)-kappaB activity is associated with enhanced tumor cell survival in multiple myeloma (MM). The function of NF-kappaB is inhibited through binding to its inhibitor, IkappaB. Release of activated NF-kappaB follows proteasome-mediated degradation of IkappaBalpha resulting from phosphorylation of the inhibitor and finally conjugation with ubiquitin. We report that myeloma tumor cells show enhanced NF-kappaB activity. In addition, these patients possess polymorphisms of IkappaBalpha at sites important in the degradation of the inhibitor protein. Exposure of myeloma cells to chemotherapy leads to an increase in IkappaBalpha phosphorylation and reduces the levels of this inhibitor of NF-kappaB function. Chemoresistant myeloma cell-lines have increased NF-kappaB activity compared to sensitive lines. An inhibitor of NF-kappaB activity, the proteasome inhibitor PS-341 (Millenium Inc, Boston, MA), showed consistent antitumor activity against chemoresistant and sensitive myeloma cells. The sensitivity of chemoresistant myeloma cells to chemotherapeutic agents was markedly increased (100,000- to 1,000,000-fold) when combined with a noncytotoxic dose of PS-341. In contrast, this combination had little growth inhibitory effect on normal hematopoietic cells. Similar effects were observed using a dominant negative super-repressor for IkappaBalpha. 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.
Berenson
J R
JR
Division of Hematology and Oncology, Beverly Modular 1, Room 100, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA.
Ma
H M
HM
Vescio
R
R
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D003546:Cysteine Endopeptidases; D004268:DNA-Binding Proteins / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D020672:I-kappa B Proteins; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology*; D010766:Phosphorylation; D011110:Polymorphism, Genetic; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D011719:Pyrazines / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001897:Boronic Acids; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D009097:Multienzyme Complexes; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011480:Protease Inhibitors; D011719:Pyrazines; D000072000:NF-KappaB Inhibitor alpha; D000069286:Bortezomib; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex