Human Myeloma Cells Undergo Differentiation and Apoptosis upon Exposure of Rosiglitazone and All-Trans Retinoic Acid Via Apoptosis Signaling Pathway Modulation

Background Myeloma cells often develop drug resistance leading to treatment failure in the patients. New agents that can overcome drug resistance through induction of apoptosis and differentiation are needed. PPARg serves as a transcription factor and functions as a heterodimer with Retinoid X receptor a (RXRa). Activation of PPARg by its ligands has shown potential anti-neoplastic effects in solid tumors. In this study, we investigate the effects of RGZ as well as combined with all trans-retinoic acid (ATRA) on human myeloma cell lines and try to address its potential mechanism.

Method U266 and RPMI-8226 cells were treated with different concentration of RGZ in the presence or absence of ATRA and various biological responses were studied by the methods of [³H] thymidine incorporation, MTT, cell cycle analysis, Annexin V-PI stanning, Wright-Gemsa staining, RT-PCR and caspase-3 activity assay.

Results We report that exposure to RGZ induced proliferation inhibition and viability loss in a dose-dependent manner in both U266 and RPMI-8226 cells. A similar exposure to RGZ also induced cell cycle arrest, cell differentiation and apoptosis of myeloma cells. A combination of RGZ with ATRA enhanced the effects of RGZ and induced cell differentiation in myeloma cells. The mRNA expressions of FLIP, XIAP and survivin were detected in both cell lines and the levels decreased significantly after cultured with RGZ, similar synergism effect of ATRA and RGZ on mRNA level of these apoptosis related genes was also observed. Caspase-3 activity increased substantially along with the increase of RGZ concentration and the addition of ATRA in culture medium shows similar synergism effect on caspase-3 activation.

Conclusion These results suggested that RGZ may represent a promising candidate for the treatment of multiple myeloma and ATRA may be useful as a combination therapy for multiple myeloma.