Synergistic interactions between the synthetic retinoid Tamibarotene (TM411) and Corticosteroids in human myeloma cells

2770 Multiple myeloma (MM) remains an incurable B-cell malignancy despite aggressive combination chemotherapy. Tamibarotene (TM411) is a synthetic retinoic acid receptor (RAR)-alpha/ -beta selective retinoid that is chemically more stable to light, heat and oxidation than All-trans retinoic acid (ATRA). It does not bind to RAR-gamma; therefore, TM411 would be expected to have fewer adverse events related to RAR-gamma. In the present study, we evaluated the anti-tumor effect of TM411 and the combination effects of TM411 and corticosteroids, one of the most effective agents against MM, using RPMI8226, MM.1S and U266 cell lines. The growth-inhibitory effects of TM411 were 2-10 fold more potent than those of ATRA with an inhibitory concentration 50% (IC50) value of about 3 nM in RPMI8226 and 10 nM in MM.1S cells. TM411 did not inhibit the cell growth of U266 cells. The expression of RAR -alpha and -beta was detected only in sensitive RPMI8226 and MM.1S cells. The combination of TM411 and corticosteroid induced remarkable synergistic effect in both RPMI8226 and MM.1S cells assessed by the in vitro isoborogram method. To elucidate the mechanism of the synergistic effect, the effect of TM411-exposure on IL-6 related molecules, which induces growth, survival and drug resistance in MM, was examined by reverse transcription polymerase chain reaction and immunoblotting. Increased expression of the IL-6 receptor, phosphorylated MAPK and Akt was observed after exposure to corticosteroid. On the other hand, TM411 inhibited the increased expression of IL-6 receptor, phosphorylated MAPK and Akt induced by corticosteroid. These findings suggested that this modification by TM411 was the possible mechanism for the synergistic effect. To further elucidate the synergistic effects, we plan to evaluate the combined therapeutic effect of drug administration on pre-existing tumors.