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

Abstract

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

Proteome analyses of the growth inhibitory effects of NCH-51, a novel histone deacetylase inhibitor, on lymphoid malignant cells

“…25 Briefly, approximately 1-10 Â 10 4 cells per 100 ml were cultured in 96-well plate in triplicates at 371C. Optical densities (OD) at 570 and 630 nm were measured with a multiplate reader.…”

Induction of cell death in adult T-cell leukemia cells by a novel IκB kinase inhibitor

“…In this study, we confirmed the constitutive activation of NFkB in HTLV-1-infected T-cell and ATL cell lines and examined the effect of a novel IKK inhibitor, 2-amino-6-(2-(cyclopropylmethoxy)-6-hydroxyphenyl)-4-piperidin-4-yl nicotinonitrile (ACHP), on the growth and survival of HTLV- 19,20 Here, we demonstrate that ACHP could efficiently induce cell growth arrest and apoptotic cell death by blocking NF-kB in ATL cells. …”

Antimyeloma effects of a novel synthetic retinoid Am80 (Tamibarotene) through inhibition of angiogenesis

“…25,26 All cell lines were cultured in RPMI 1640 medium containing 10% fetal bovine serum (FBS), streptomycin, and penicillin. Recombinant human IL-6 (Diaclone research, Besancon, France) was added at 10 ng/ml to the medium of ILKM-2, ILKM-3 and ILKM-8.…”