Genistein down‐regulates the constitutive activation of nuclear factor‐κB of bone marrow stromal cells in multiple myeloma, leading to suppression of gene expression and proliferation

Bone marrow stromal cells (BMSCs) play a central role in human multiple myeloma(MM) cell survival and proliferation. We explored the possibility of using BMSCs as a target for MM treatment using genistein, a chemopreventive agent with little or no toxicity in humans. NF-κB was constitutively active in BMSCs and genistein down-regulated NF-κB in BMSCs as measured by an electrophoretic mobility gel shift assay. BMSCs also showed constitutively active Akt phosphorylation that was suppressed by genistein. Genistein also down-regulated the expression of NF-κB-regulated gene products, including bcl-2, bcl-xl, Cyclin D1, IL-6, and ICAM-1, which was associated with the suppression of BMSC proliferation. MM cells can survive if co-cultured with BMSCs, suggesting that the bone marrow microenvironment is important. However, genistein-treated BMSCs provide little support to MM cells. Overall, our results indicate that genistein down-regulates NF-κB and phospho-Akt of BMSCs in human myeloma, leading to the suppression of gene expression of bcl-2, bcl-xl, Cyclin D1, IL-6, and ICAM-1 suppression proliferation, thus providing a potential new target for the treatment of MM. Drug Dev Res 69:219–225, 2008. © 2008 Wiley-Liss, Inc.