CDDO-imidazolide mediated inhibition of malignant cell growth in Waldenström macroglobulinemia.
Waldenström macroglobulinemia (WM) is a B-cell malignancy that remains incurable. Synthetic triterpenoids (ST), 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO), its methyl ester derivative (CDDO-Me) and imidazolide derivative (CDDO-Im) induce cell death and inhibit growth of various malignancies and hold promise as treatment for cancer patients. We examined the therapeutic potential of these compounds in WM. All three forms of CDDO induced equal toxicity in BCWM.1 cells. In malignant B cells from WM patients, CDDO-Im induced the greatest toxicity. CDDO-Im inhibited proliferation at nanomolar concentrations and arrested the cells in G0/G1. CDDO-Im induced apoptotic cell death that was partially abolished in the presence of caspase inhibitor. CDDO-Im also inhibited survival pathways that have been shown to be important in WM. Overall, our data suggest that ST are likely to provide therapeutic efficacy for WM patients.
Elsawa
Sherine F
SF
Division of Hematology and Internal Medicine, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Novak
Anne J
AJ
Grote
Deanna
D
Konopleva
Marina
M
Andreeff
Michael
M
Witzig
Thomas E
TE
Ansell
Stephen M
SM
D000199:Actins / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology; D001706:Biopsy; D001854:Bone Marrow Cells / Q000473:pathology; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D009369:Neoplasms / Q000473:pathology*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D014315:Triterpenes / Q000494:pharmacology; D008258:Waldenstrom Macroglobulinemia / Q000473:pathology*
C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D000199:Actins; D007093:Imidazoles; D014315:Triterpenes; D009828:Oleanolic Acid; D053181:Caspase 8; D053453:Caspase 9