Inhibition of myeloma cell growth by dexamethasone and all-trans retinoic acid: synergy through modulation of interleukin-6 autocrine loop at multiple sites.

摘要: Interleukin-6 (IL-6)/IL-6 receptor (IL-6R) plays a major role in autocrine/paracrine growth regulation of myeloma cells. We investigated the effect dexamethasone and all-trans retinoic acid, previously shown to modulate IL-6/IL-6R, on vitro human cell line, OPM-2. Both agents inhibited clonogenic 3H-thymidine incorporation concentration-dependent fashion. Isobologram median analysis showed strong synergy between these two with combination index range 0.2 0.6. decreased labeling fraction S G2/M phases, suggesting block G1-S phase transition. The was stimulated by exogenous IL-6 monoclonal antibody IL-6, an autocrine function IL-6. but not acid completely reversed Dexamethasone increased, while reduced, IL-6R gp130 mRNA expression. Their caused net reduction mRNA. Cellular density altered correspondingly without changes binding affinity. expression reduced combination, affected alone. However, secretion into culture supernatant abolished both agents. A survey 4 additional cells that 1 sensitive both, one agent only, 2 were resistant both. study demonstrates possibility regulating through modulation IL-6/IL-6R loop principle achieving synergistic blocking this at multiple sites.