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.
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.
Molostvov
G
G
Department of Reproductive and Vascular Biology, S102 West Wing Extension, Medical School, University of Birmingham, Birmingham B15 2TT, UK. g.molostvov@bham.ac.uk
Morris
A
A
Rose
P
P
Basu
S
S
Muller
G
G
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D018920:Coculture Techniques; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003864:Depression, Chemical; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000032:analysis / Q000378:metabolism; D009101:Multiple Myeloma / Q000378:metabolism*; D013792:Thalidomide / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D016207:Cytokines; D015850:Interleukin-6; D042461:Vascular Endothelial Growth Factor A; D013792:Thalidomide