DHMEQ, a new NF-kappaB inhibitor, induces apoptosis and enhances fludarabine effects on chronic lymphocytic leukemia cells.
Chronic lymphocytic leukemia (CLL) is a low-grade lymphoid malignancy incurable with conventional modalities of chemotherapy. Strong and constitutive nuclear factor kappa B (NF-kappaB) activation is a characteristic of CLL cells. We examined the effects of a new NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on CLL cells. Dehydroxymethylepoxyquinomicin completely abrogated constitutive NF-kappaB activity and induced apoptosis of CLL cells. Apoptosis induced by DHMEQ was accompanied by downregulation of NF-kappaB-dependent antiapoptotic genes: c-IAP, Bfl-1, Bcl-X(L) and c-FLIP. Dehydroxymethylepoxyquinomicin also inhibited NF-kappaB induced by CD40 and enhanced fludarabine-mediated apoptosis of CLL cells. Results of this study suggest that inhibition of constitutive and inducible NF-kappaB by DHMEQ in combination with fludarabine is a promising strategy for the treatment of CLL.
Horie
R
R
Department of Hematology, School of Medicine, Kitasato University, Sagamihara, Kanagawa, Japan. rhorie@med.kitasato-u.ac.jp
Watanabe
M
M
Okamura
T
T
Taira
M
M
Shoda
M
M
Motoji
T
T
Utsunomiya
A
A
Watanabe
T
T
Higashihara
M
M
Umezawa
K
K
D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D019013:CD40 Antigens / Q000187:drug effects; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003512:Cyclohexanones / Q000494:pharmacology*; D015536:Down-Regulation; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000187:drug effects / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051020:bcl-X Protein / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; C096816:BCL2-related protein A1; D001549:Benzamides; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D019013:CD40 Antigens; C506386:CFLAR protein, human; D003512:Cyclohexanones; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C464444:dehydroxymethylepoxyquinomicin; D020169:Caspases; D014740:Vidarabine; C024352:fludarabine