Aldo-keto reductases contribute to melphalan resistance in MM cells.

(A), Diagram showing markedly up-regulated levels of the AKR1C family in both SILAC and mRNA analyses, whereas members of other AKR subfamilies are not significantly altered. (B), Western analysis confirmed up-regulation of AKR1C2 and C3, but not C4. (C), Bar diagram illustrating the effects of AKR inhibitors flufenamic acid (FA, 70 μM), ursodeoxycholate (UDC, 16 μM) and indomethacin (IM, 16 μM) when administered in the presence or absence of 2.5 μM melphalan. (D), Bar diagram illustrating that co-treatment of the myeloma cells with NSAIDs acetylsalisylic acid (ASA) or ibuprofen (Ibu) with melphalan does not reverse the melphalan-resistant phenotype. (E), Western analysis demonstrating strong induction of AKR1C3 and a weaker induction of AKR1C2 in the melphalan-sensitive cells (upper panel) subsequent to 20 h incubation in various concentrations of methyl glyoxal (MG). MG treatment did not affect the AKR1C levels in the resistant cells (lower panel). (F), Bar diagram illustrating that that MG pretreatment (1μM) induced a melphalan-resistant phenotype in the parental RPMI8226 cells similar to that of the resistant LR5 cells.