The Novel, Proteasome-Independent NF-κB Inhibitor V1810 Induces Apoptosis and Cell Cycle Arrest in Multiple Myeloma and Overcomes NF-κB–Mediated Drug Resistance

Evidence is increasing that aberrant NF-κB activation is crucial for multiple myeloma pathophysiology and a promising target for new antimyeloma therapies. In this study, we assessed the in vitro antimyeloma activity of the novel NF-κB inhibitor V1810. Pharmacokinetics and toxicity were studied in vivo . In mice, V1810 plasma concentrations of 10 μmol/L can be reached without relevant toxicity. At this concentration, V1810 potently induces apoptosis in all four multiple myeloma cell lines assessed (IC50 = 5–12 μmol/L) as well as in primary multiple myeloma cells (IC50 = 5–40 μmol/L). Apoptosis induced by V1810 is associated with proteasome-independent inhibition of NF-κB signaling (41% relative reduction), downregulation of Mcl-1, and caspase 3 cleavage. In OPM2, U266, and RPMI-8226 cells, induction of apoptosis is accompanied by cell cycle arrest. Western blots revealed downregulation of Cdk4 as well as cyclin D1 (U266) or cyclin D2 (OPM2, NCI-H929, RPMI-8226), but not cyclin D3. Consistently, retinoblastoma protein was found to be hypophosphorylated. Furthermore, V1810 reverses NF-κB activation induced by the genotoxic drugs melphalan and doxorubicin. V1810 and melphalan synergistically decrease multiple myeloma cell viability. Taken together, the novel, proteasome-independent NF-κB inhibitor V1810 induces apoptosis and cell cycle arrest in multiple myeloma cells at a concentration range that can be achieved in vivo . Moreover, V1810 reverses NF-κB activation by alkylating drugs and overcomes NF-κB–mediated resistance to melphalan. Mol Cancer Ther; 9(2); 300–10