Alkylating agents induce activation of NFkappaB in multiple myeloma cells.

Multiple myeloma is still not curable and drug combination strategies are currently being evaluated in order to achieve high remission rates with tolerable toxicity. Bortezomib has been shown to exert inhibitory effects on NFkappaB activity. NFkappaB in turn is known to be activated by cytokines, growth factors and by cellular adhesion to bone marrow stromal cells and represents an important mediator of primary and secondary drug resistance in multiple myeloma that confers to proliferation and survival. In this study we confirm that bortezomib sensitized MM cells to the DNA-damaging drugs melphalan and doxorubicin. Further, we demonstrate that the sole incubation of MM cells with melphalan or doxorubicin leads to a vast activation of NFkappaB activity. Additionally, we show that the co-incubation of bortezomib with melphalan or doxorubicin reduces activation of NFkappaB. These data suggest that the drug-sensitizing effect of bortezomib on MM cells is due to inhibition of melphalan- and doxorubicin-induced activation of NFkappaB activity. This study, therefore, supports the idea of combining a NFkappaB inhibitor with alkylating drugs in the therapy of multiple myeloma.