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Growth Inhibition of Multiple Myeloma Cells by a Novel IB Kinase Inhibitor

Departments of ¹ Molecular and Cellular Biology, and ² Internal Medicine and Molecular Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan and Departments of ³ Chemistry and ⁴ Biology, Research Center Kyoto, Bayer Yakuhin, Ltd., Kyoto, Japan

Requests for reprints: Takashi Okamoto, 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. Phone: 81-52-853-8205; Fax: 81-52-859-1235; E-mail: tokamoto{at}med.nagoya-cu.ac.jp.

Involvement of nuclear factor-B (NF-B) in cell survival and proliferation of multiple myeloma has been well established. In this study we observed that NF-B 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-B in addition to the phosphorylation of IB and the activation of NF-B DNA binding and that various target genes of NF-B including bcl-x_L, XIAP, c-IAP1, cyclin D1, and IL-6 are up-regulated. We then examined the effect of a novel IB 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 IC₅₀ values ranging from 18 to 35 µmol/L concomitantly with inhibition of the phosphorylation of IB/p65 and NF-B DNA-binding, down-regulation of the NF-B 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 IB 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-B.

Key Words: NF-B • apoptosis • chemotherapy

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