Myeloma cell growth arrest, apoptosis, and interleukin-6 receptor modulation induced by EB1089, a vitamin D3 derivative, alone or in association with dexamethasone
Puthier, D.; Bataille, R.; Barillé, S.; Mellerin, M.P.; Harousseau, J.L.; Ponzio, A.; Robillard, N.; Wijdenes, J.; Amiot, M.
Blood 88(12): 4659-4666
We have previously shown that malignant plasma cells expressed the specific receptor for 1,25-dihydroxyvitamin D-3 and that this derivative could significantly inhibit the proliferation of such malignant cells. More recently, new vitamin D-3 derivatives have been generated with extraordinarily potent inhibitory effects on leukemic cell growth in vitro. These new data prompted us to reinvestigate the capacity of such new vitamin D-3 derivatives to inhibit myeloma cell growth in comparison with that of dexamethasone, a potent antitumoral agent in multiple myeloma. In the current study, we show that EB1089, a new vitamin D-3 derivative, (1) induces G1 growth arrest of human myeloma cells, which is only partially reversed by interleukin-6 (IL-6); (2) induces apoptosis in synergy with dexamethasone, IL-6, leukemia- inhibitory factor, and Oncostatin M, with an agonistic anti-gp130 monoclonal antibody being unable to prevent this apoptosis; (3) downregulates both the gp80 (ie, the alpha chain of the IL-6 receptor (IL-6R-alpha)) expression on malignant plasma cells and the production of soluble IL-6R-alpha, and finally (4) inhibits the deleterious upregulation of gp80 expression induced by dexamethasone while limiting the dexamethasone-induced upregulation of gp130 expression. Considering that these in vitro effects of EB1089 have been observed at doses obtainable in vivo (without hypercalcemic effects), our present data strongly suggest that EB1089 could have a true interest in the treatment of multiple myeloma, especially in association with dexamethasone.