dehydroxymethylepoxyquinomicin and fludarabine

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.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; bcl-X Protein; Benzamides; CASP8 and FADD-Like Apoptosis Regulating Protein; Caspases; CD40 Antigens; Cell Line, Tumor; Cell Survival; Cyclohexanones; Down-Regulation; Drug Synergism; Female; Humans; Inhibitor of Apoptosis Proteins; Intracellular Signaling Peptides and Proteins; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Minor Histocompatibility Antigens; NF-kappa B; Proto-Oncogene Proteins c-bcl-2; Tumor Cells, Cultured; Vidarabine