Influx and Efflux Transport as Determinants of Melphalan Cytotoxicity: Resistance to Melphalan in Overexpressing Tumor Cell Lines

Annett Kühne , Mladen Vassilev Tzvetkov , Yohannes Hagos , Hermann Lage , Gerhard Burckhardt , Jürgen Brockmöller

There is considerable variation in efficacy of melphalan therapy in multiple myeloma (MM) and other hematopoietic tumors. We hypothesized that this may be due to variations in the expression of influx and efflux transporters of melphalan. We measured the expression of the influx transporters , , and and the efflux transporters , and by quantitative RT-PCR and related their expression to the intracellular accumulation and cytotoxicity of melphalan in 7 MM and 21 non-MM hematopoietic tumor cell lines. Variation in the intracellular accumulation accounted for nearly half of the variation in the cytotoxicity of melphalan in MM cell lines (r=0.47, p=0.04). High expression of the efflux transporter was associated with low intracellular accumulation and low cytotoxicity of melphalan (r=0.56, p=0.03 and r=0.62, p=0.02, respectively). The effect was reversed by the MDR1 inhibitor cyclosporine. In addition, the -overexpressing HL-60 cell line showed 10-fold higher resistance to melphalan than the non--expressing one. The resistance was reversed again by cyclosporine and by MDR1-specific shRNA.

Mots clés: MM; MDR1; MRP1; LAT; TAT; BCRP; melphalan transport; P-glycoprotein; LAT1; multiple myeloma

Annett Kühne, Mladen Vassilev Tzvetkov, Yohannes Hagos, Hermann Lage, Gerhard Burckhardt, et al.. Influx and Efflux Transport as Determinants of Melphalan Cytotoxicity: Resistance to Melphalan in Overexpressing Tumor Cell Lines. Biochemical Pharmacology, 2009, 78 (1), pp.45. ⟨10.1016/j.bcp.2009.03.026⟩. ⟨hal-00493510⟩