The role of nuclear factor-κb in the biology and treatment of multiple myeloma

Abstract

Increased nuclear factor (NF)-κB activity is associated with enhanced tumor cell survival in multiple myeloma (MM). The function of NF-κB is inhibited through binding to its inhibitor, Iκb. Release of activated NF-κB follows proteasome-mediated degradation of IκBα resulting from phosphorylation of the inhibitor and finally conjugation with ubiquitin. We report that myeloma tumor cells show enhanced NF-κB activity. In addition, these patients possess polymorphisms of IκBα at sites important in the degradation of the inhibitor protein. Exposure of myeloma cells to chemotherapy leads to an increase in IκBα phosphorylation and reduces the levels of this inhibitor of NF-kB function. Chemoresistant myeloma cell-lines have increased NF-κB activity compared to sensitive lines. An inhibitor of NF-κB 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 IκBα. 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.