ABSTRACT
Multiple myeloma (MM) is a fatal lymphoid malignancy that is incurable with conventional modalities of chemotherapy. Strong and constitutive activation of nuclear factor kappa B (NF-kappaB) is a common characteristic of MM cells. In our study we successfully target NF-kappaB with a novel NF-kappaB inhibitor dehydroxymethylepoxyquinomycin (DHMEQ). DHMEQ completely abrogates constitutive NF-kappaB activity and induces apoptosis of MM cells, whereas control peripheral blood mononuclear cells (PBMC) are resistant to NF-kappaB inhibition and apoptosis by DHMEQ treatment. DHMEQ inhibition of NF-kappaB triggers activation of caspases 8 and 9, as well as G0/G1 cell cycle arrest accompanied by downregulation of antiapoptotic genes Bcl-XL and c-FLIP and cell cycle progression gene cyclins D1 and D2. DHMEQ-mediated inhibition of vascular endothelial growth factor (VEGF) production in MM cells raises the possibility that DHMEQ abrogates the autocrine VEGF loop and enhances its antitumor effects by inhibiting neovascularization in the bone marrow. Using an in vivo NOD/SCID/gammac(null) (NOG) mice model, we show that DHMEQ has a potent inhibitory effect on the growth of MM cells. Compared to other compounds having the potential to inhibit NF-kappaB, DHMEQ is a unique compound that blocks the translocation of NF-kappaB p65 into the nucleus and selectively targets NF-kappaB activated in tumor cells. Therefore, our study presents a new molecular target therapy in MM.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Benzamides/pharmacology , Cyclohexanones/pharmacology , Multiple Myeloma/drug therapy , NF-kappa B/antagonists & inhibitors , Animals , CASP8 and FADD-Like Apoptosis Regulating Protein , Calcium-Binding Proteins , Caspase 3 , Caspase 8 , Caspase 9 , Caspases/metabolism , Cell Line, Tumor , Cyclin D , Cyclin D1/metabolism , Cyclins/metabolism , Disease Models, Animal , Down-Regulation , Enzyme Activation/drug effects , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Membrane Glycoproteins , Mice , Mice, Inbred NOD , Mice, SCID , Multiple Myeloma/metabolism , Nerve Tissue Proteins , Proto-Oncogene Proteins c-bcl-2/metabolism , Synaptotagmin I , Synaptotagmins , Translocation, Genetic/drug effects , Vascular Endothelial Growth Factor A/antagonists & inhibitors , bcl-X ProteinABSTRACT
We observed massive hemolysis after allogeneic peripheral blood stem cell transplantation with minor ABO incompatibility (the donor was group O and the recipient group A). The patient was a 21-year-old man diagnosed as having Philadelphia chromosome-positive chronic myelogenous leukemia. On day 7 post-transplant, there was abrupt onset of massive hemolysis necessitating supportive treatment with transfusions. During the allogeneic peripheral blood stem cell transplantation the patient had received 2 x 10(8) CD3 positive cells/kg and 7.8 x 10(7) CD19 positive cells/kg donor lymphocytes with stem cells. The present case shows that in allogeneic peripheral blood stem cell transplantation with ABO incompatibility, severe hemolysis occurs early after transplantation presumably due to the transfusion of a large number of lymphocytes.
