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The effects of selective cytokine inhibitory drugs (CC‐10004 and CC‐1088) on VEGF and IL‐6 expression and apoptosis in myeloma and endothelial cell co‐cultures
Author(s) -
Molostvov G.,
Morris A.,
Rose P.,
Basu S.,
Muller G.
Publication year - 2004
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1046/j.1365-2141.2003.04777.x
Subject(s) - apoptosis , multiple myeloma , umbilical vein , cytokine , cell culture , cancer research , vascular endothelial growth factor , endothelial stem cell , microbiology and biotechnology , in vitro , biology , immunology , medicine , vegf receptors , biochemistry , genetics
Summary Myeloma cells and human umbilical vein endothelial cells (HUVECs) were co‐cultured to model in vitro the interactions between myeloma and endothelium, and treated with thalidomide and two selective cytokine inhibitory drugs (SelCIDs, phosphodiesterase‐4 inhibitors). Flow cytometry and enzyme‐linked immunosorbent assay were used to assess production of two key cytokines – vascular endothelial growth factor (VEGF) and interleukin‐6 (IL‐6) – and apoptosis in co‐cultured HUVECs and myeloma cells. VEGF was produced by both myeloma cells and HUVECs, while IL‐6 was almost exclusively produced by endothelial cells. In co‐culture, there was significant up‐regulation of VEGF and IL‐6 production compared with the sum of separate myeloma and endothelial cell cultures. SelCIDs markedly inhibited production of both cytokines in co‐cultures, with CC‐10004 being more potent than CC‐1088. In addition, SelCIDs induced myeloma cell apoptosis. Apoptosis in co‐cultured myeloma cells was significantly lower than in those cultured separately, suggesting that co‐culture partially protected myeloma cells from drug‐induced apoptosis. This protective effect was probably due to IL‐6 produced by endothelial cells in co‐culture as addition of anti‐IL‐6 neutralizing antibody, but not anti‐VEGF antibody, abrogated it. In conclusion, SelCIDs can exert their anti‐myeloma activity through two mechanisms, i.e. inhibition of VEGF and IL‐6 production by interacting myeloma and endothelium and induction of myeloma cell apoptosis.