| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 2134596 | Experimental Hematology | 2010 | 11 Pages |
ObjectiveDifferentiation-inducing therapy by agents such as 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) represents a useful approach for the treatment of acute myelogenous leukemia (AML). We previously showed that Gemini-23-yne-26,27-hexafluoro-D3 inhibited the proliferation of MCF-7 breast cancer cells in association with inhibition of the mammalian target of rapamycin (mTOR) signaling. This study explored the drug interaction of 1,25(OH)2D3 and rapamycin analog RAD001 (everolimus) in AML cells.Materials and MethodsEffects of RAD001 and 1,25-(OH)2D3 on the proliferation and differentiation of U937 cells were assessed by colony-forming assay and quantification of CD11b cell surface antigens and their endocytic capability, respectively. Effects of RAD001 and 1,25-(OH)2D3 on Akt/mTOR complex-1 (mTORC1) signaling and cell-cycle−related molecules were explored by Western blot analysis. The reporter gene and chromatin immunoprecipitation assays were employed to examine the effects of RAD001 and 1,25-(OH)2D3 on the promoter of the p21waf1 gene. U937 murine xenograft model was utilized to explore the effects of RAD001 and 1,25-(OH)2D3 in vivo.ResultsRAD001 potentiated the ability of 1,25(OH)2D3 to induce growth arrest and differentiation of AML cells in parallel with downregulation of the levels of p-S6K and p-4E-BP1, substrates of mTORC1. In addition, RAD001 significantly enhanced 1,25(OH)2D3-mediated transcriptional activity of p21waf1 in association with increased levels of the acetylated forms of histone H3 and vitamin D receptor bound to the p21waf1 promoter in U937 cells. Moreover, RAD001 (3 mg/kg, every another day) significantly enhanced 1,25(OH)2D3-induced growth inhibition of U937 tumor xenografts in nude mice without adverse effects.ConclusionsConcomitant administration of 1,25(OH)2D3 and the mTORC1 inhibitor may be a promising treatment strategy for individuals with AML.
