The novel, proteasome-independent NF-kappaB inhibitor V1810 induces apoptosis and cell cycle arrest in multiple myeloma and overcomes NF-kappaB-mediated drug resistance.
Evidence is increasing that aberrant NF-kappaB 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-kappaB inhibitor V1810. Pharmacokinetics and toxicity were studied in vivo. In mice, V1810 plasma concentrations of 10 micromol/L can be reached without relevant toxicity. At this concentration, V1810 potently induces apoptosis in all four multiple myeloma cell lines assessed (IC(50) = 5-12 micromol/L) as well as in primary multiple myeloma cells (IC(50) = 5-40 micromol/L). Apoptosis induced by V1810 is associated with proteasome-independent inhibition of NF-kappaB 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-kappaB 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-kappaB 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-kappaB activation by alkylating drugs and overcomes NF-kappaB-mediated resistance to melphalan.
Meinel
Felix G
FG
Department of Hematology and Oncology, Medizinische Klinik Innenstadt, Klinikum der Universität München, Munich, Germany.
Mandl-Weber
Sonja
S
Baumann
Philipp
P
Leban
Johann
J
Schmidmaier
Ralf
R
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001562:Benzimidazoles / Q000494:pharmacology*; D002453:Cell Cycle; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D008558:Melphalan / Q000494:pharmacology; D051379:Mice; D009101:Multiple Myeloma / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D013844:Thiazoles / Q000494:pharmacology*
C553325:2-(1-thieno(3,2-d)pyrimidin-4-ylpiperidin-4-yl)thiazole-4-carboxylic acid (6-benzoyl-1H-benzoimidazol-2-yl)amide; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D013844:Thiazoles; D046988:Proteasome Endopeptidase Complex; D008558:Melphalan