Dehydroxymethylepoxyquinomicin, a novel nuclear factor-kappaB inhibitor, induces apoptosis in multiple myeloma cells in an IkappaBalpha-independent manner.
Nuclear factor-kappaB (NF-kappaB) is constitutively activated in multiple myeloma cells. Several proteasome inhibitors have been shown to be effective against multiple myeloma and may act by inhibiting degradation of IkappaBalpha. Here, we examined the biological effects of a new type of NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), which is reported to directly inhibit the cytoplasm-to-nucleus translocation of NF-kappaB. A multiple myeloma cell line, 12PE, which is defective for IkappaBalpha protein, was utilized to determine if IkappaBalpha is concerned with the action of DHMEQ. Meanwhile, U266 was used as a multiple myeloma cell line with normal IkappaBalpha. A proteasome inhibitor, gliotoxin, which is an inhibitor of degradation of phosphorylated IkappaBalpha, failed to inhibit translocation of NF-kappaB in 12PE. In contrast, DHMEQ equally inhibited translocation of NF-kappaB to the nucleus and induced apoptosis to both multiple myeloma cell lines, suggesting that apoptosis resulting from DHMEQ is IkappaBalpha independent. DHMEQ also induced apoptosis in freshly isolated multiple myeloma cells. After DHMEQ treatment, cleavage of caspase-3 and down-regulation of cyclin D1 were observed in both cell lines. In addition, administration of DHMEQ resulted in a significant reduction in tumor volume in a plasmacytoma mice model compared with control mice. Our results show that DHMEQ could potentially be a new type of molecular target agent for multiple myeloma.
Tatetsu
Hiro
H
Department of Hematology, Kumamoto University School of Medicine, Japan.
Okuno
Yutaka
Y
Nakamura
Miki
M
Matsuno
Fumihiko
F
Sonoki
Takashi
T
Taniguchi
Izumi
I
Uneda
Shima
S
Umezawa
Kazuo
K
Mitsuya
Hiroaki
H
Hata
Hiroyuki
H
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D019938:Cyclin D1 / Q000187:drug effects / Q000378:metabolism; D003512:Cyclohexanones / Q000494:pharmacology*; D015536:Down-Regulation; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D015778:Minor Histocompatibility Antigens; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C096816:BCL2-related protein A1; D001549:Benzamides; D003512:Cyclohexanones; D020672:I-kappa B Proteins; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; C464444:dehydroxymethylepoxyquinomicin; D019938:Cyclin D1; D000072000:NF-KappaB Inhibitor alpha; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases