Because of the central role of transcription factor nuclear factor-kappaB (NF-kappaB) in cell survival and proliferation in human multiple myeloma, the possibility of using it as a target for myeloma treatment was explored using genistein, an agent known to have very little or no toxicity in humans. It was found that NF-kappaB was constitutively active in two human myeloma cell lines examined and that genistein, a chemopreventive agent, down-regulated NF-kappaB in two cell lines as indicated by the electrophoretic mobility gel shift assay and prevented the nuclear retention of p65 as shown by immunocytochemistry. Two myeloma cell lines showed constitutively active Akt phosphorylation. Genistein suppressed the constitutive Akt phosphorylation. Genistein also down-regulated the expression of NF-kappaB-regulated gene products, including bcl-2, bcl-xl, cyclin D1 and ICAM-1. This led to the suppression of proliferation and induction of apoptosis. Overall, the results indicate that genistein down-regulates NF-kappaB and phospho-Akt in human myeloma cells, leading to the suppression of proliferation and induction of apoptosis, thus providing the molecular basis for the treatment of myeloma patients with this pharmacologically safe agent.
(c) 2008 John Wiley & Sons, Ltd.