Long-Term Arsenic Trioxide (ATO) Treatment Changes Multiple Myeloma (MM) Cells Micro-RNA and RNA Expression Profiles

Although the preliminary results of treating refractory and relapsed multiple myeloma patents with ATO are promising, the data suggest that the resistance to ATO treatment frequently occurs (57 to 79%). We treated MM cells RPMI8226 with long-term low dosage ATO (0.5 μM) and harvested the ATO resistant cells. ATO resistant cells IC50 is 4 times higher and ATO resistant cells formed 2 times more colonies with 0.75 μM ATO treatment than parental RPMI8226. P-p38 MAPK, Bcl-2, XIAP and survivin were elevated to a relatively high level in ATO resistant cells under continuous ATO stress. We have established a custom designed miRNA microarray printed with a comprehensive panel of miRNAs in miRBase version 9.0 (238 mmu-mirs) and miRNA predictions including 2617 MED-MIR predictions, 321 ‘Cand” predictions discovered through a strategy based on pylogenetice-shadowing, 129 ‘MIR” predictions discovered through a search for miRNA targets in 3′ UTR sequences. We used this miRNA array to probe the miRNA expression profiles of RPMI8226 and resistant cells and observed differences in miRNA expression between the two lines. We also performed oligonucleotide microarray analysis using HG-U133 plus 2.0 array to screen the differential gene expression. Results showed that ATO resistant cells repressed the expression of has-miR-181a, has-miR-181b, has-let-7i, has-miR-19b, has-miR-18a, has-miR-20a and has-miR222. On the other hand, LMAN1, NPGPx, HSP73 and EIF1 genes expression were up-regulated. These data revealed the preliminary mechanism how MM cells adapt to ATO and provide potential targets to overcome the ATO in MM therapy.