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Inhibition of myeloma cell growth by dexamethasone and all-trans retinoic
acid: synergy through modulation of interleukin-6 autocrine loop at
multiple sites
YH Chen, P Desai, RT Shiao, D Lavelle, A Haleem and J Chen
Department of Medicine, University of Illinois College of Medicine, Chicago
60612, USA.
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 of dexamethasone and all-trans retinoic acid, previously shown to
modulate IL-6/IL-6R, on the in vitro growth of a human myeloma cell line,
OPM-2. Both agents inhibited the clonogenic growth and 3H- thymidine
incorporation in a concentration-dependent fashion. Isobologram and median
effect analysis showed a strong synergy between these two agents with a
combination index in the range of 0.2 to 0.6. Both agents decreased the
labeling index and the cell fraction in S and G2/M phases, suggesting a
block in G1-S phase transition. The clonogenic growth was stimulated by
exogenous IL-6 and was inhibited by monoclonal antibody to IL-6, suggesting
an autocrine function of IL-6. The effect of dexamethasone but not
all-trans retinoic acid was completely reversed by exogenous IL-6.
Dexamethasone increased, while all-trans retinoic acid reduced, IL-6R but
not gp130 mRNA expression. Their combination caused a net reduction in
IL-6R mRNA. Cellular IL-6R density was altered correspondingly without
changes in the binding affinity. IL-6 mRNA expression was reduced by
dexamethasone and the combination, but was not affected by retinoic acid
alone. However, IL-6 secretion into culture supernatant was abolished by
both agents. A survey of 4 additional human myeloma cells showed that 1 was
sensitive to both, 1 was sensitive to one agent only, and 2 were resistant
to both. The study demonstrates the possibility of regulating myeloma cell
growth through modulation of IL-6/IL-6R autocrine/paracrine loop and the
principle of achieving a synergistic effect by blocking this loop at
multiple sites.
Volume 87,
Issue 1,
pp. 314-323,
01/01/1996
Copyright © 1996 by The American Society of Hematology
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