Growth inhibition of multiple myeloma cells by a novel IkappaB kinase inhibitor.
Involvement of nuclear factor-kappaB (NF-kappaB) in cell survival and proliferation of multiple myeloma has been well established. In this study we observed that NF-kappaB is constitutively activated in all human myeloma cell lines, thus confirming the previous studies. In addition, we found the phosphorylation of p65 subunit of NF-kappaB in addition to the phosphorylation of IkappaBalpha and the activation of NF-kappaB DNA binding and that various target genes of NF-kappaB including bcl-x(L), XIAP, c-IAP1, cyclin D1, and IL-6 are up-regulated. We then examined the effect of a novel IkappaB kinase inhibitor, 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl nicotinonitrile (ACHP). When myeloma cells were treated with ACHP, the cell growth was efficiently inhibited with IC(50) values ranging from 18 to 35 mumol/L concomitantly with inhibition of the phosphorylation of IkappaBalpha/p65 and NF-kappaB DNA-binding, down-regulation of the NF-kappaB target genes, and induction of apoptosis. In addition, we observed the treatment of ACHP augmented the cytotoxic effects of vincristine and melphalan (l-phenylalanine mustard), conventional antimyeloma drugs. These findings indicate that IkappaB kinase inhibitors such as ACHP can sensitize myeloma cells to the cytotoxic effects of chemotherapeutic agents by blocking the antiapoptotic nature of myeloma cells endowed by the constitutive activation of NF-kappaB.
Sanda
Takaomi
T
Department of Molecular and Cellular Biology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-08601, Japan.
Iida
Shinsuke
S
Ogura
Hiroka
H
Asamitsu
Kaori
K
Murata
Toshiki
T
Bacon
Kevin B
KB
Ueda
Ryuzo
R
Okamoto
Takashi
T
D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D004247:DNA / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology*; D009101:Multiple Myeloma / Q000473:pathology*; D016328:NF-kappa B / Q000494:pharmacology*; D009539:Nicotinic Acids / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology*; D010766:Phosphorylation; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
C501280:2-amino-6-(2-(cyclopropylmethoxy)-6-hydroxyphenyl)-4-piperidin-4-yl nicotinonitrile; D016207:Cytokines; D020672:I-kappa B Proteins; D016328:NF-kappa B; D009539:Nicotinic Acids; D009570:Nitriles; D004247:DNA