Genistein down-regulates the constitutive activation of nuclear factor-kappaB in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis.

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.

Circulating endothelial progenitor cells in multiple myeloma: implications and significance.

Angiogenesis governs the progression of multiple myeloma (MM). Circulating endothelial cells (CECs) contribute to angiogenesis and comprise mature ECs and endothelial progenitor cells (EPCs). The present study sought to characterize CECs and their relation to disease activity and therapeutic response in 31 consecutive patients with MM. CECs, identified as CD34(+)/CD146(+)/CD105(+)/CD11b(-) cells, were 6-fold higher in patients compared to controls and correlated positively with serum M protein and beta(2)-microglobulin. Circulating EPCs displayed late colony formation/outgrowth and capillary-like network formation on matrigel; these processes were inhibited after effective thalidomide treatment. Co-expression of vascular endothelial growth factor receptor-2 (KDR) and CD133 characterized EPCs in MM, and KDR mRNA elevations correlated with M protein levels. In vitro exposure of ECs to thalidomide or its derivative CC-5013 inhibited gene expression of the receptors for transforming growth factor-beta and thrombin. Thus, elevated levels of CECs and EPCs covary with disease activity and response to thalidomide, underscoring the angiogenic aspect of MM and suggesting that angioblastlike EPCs are a pathogenic biomarker and a rational treatment target in MM. The results also highlight the anti-angiogenic properties of thalidomide and CC-5013 and further elucidate possible mechanisms of their effectiveness against MM. (Blood. 2005;105:3286-3294).