Differential involvement of glutathione S‐transferase mu 1 and multidrug resistance protein 1 in melanoma acquired resistance to vinca alkaloids

On account of its extreme intrinsic resistance to apoptosis and of its strong ability to become chemoresistant after a primary response to drugs, malignant melanoma ( MM ) is still a therapeutic challenge. We previously showed that glutathione S‐transferase mu 1 ( GSTM 1) acts in synergy with multidrug resistance protein 1 ( MRP 1) to protect GSTM 1‐transfected human CAL 1 melanoma cells from toxic effects of vincristine ( VCR ). Herein, we investigated the role of these proteins in the acquired resistance of CAL 1 cells to vinca alkaloids ( VA s). Resistant lines were established by continuous exposure (>1 year) of parental CAL 1‐wt cells to VCR , vindesine ( VDS ), or vinorelbine ( VRB ): CAL 1R‐ VCR , CAL 1R‐ VDS , CAL 1R‐ VRB , respectively. All resistant lines displayed more than 10‐fold increase in resistance to their selection VA , and specifically expressed GSTM 1. Suggesting a direct interaction between this protein and VA s, each VA specifically decreased the GSTM 1‐mediated glutathione conjugation activity in cell lysates. Curcumin ( GSTM 1 inhibitor), BSO (glutathione synthesis inhibitor), and MK 571 ( MRP 1 inhibitor) considerably reversed the acquired resistance to VCR and VDS , but not to VRB . Microarray data analysis revealed similar gene expression patterns of CAL 1R‐ VCR and CAL 1R‐ VDS , and a distinct one for CAL 1R‐ VRB . These data suggest a differential involvement of GSTM 1 and MRP 1 in acquired resistance to VA s. A coordinated expression and activity of GSTM 1 and MRP 1 is required to protect CAL 1 cells from VCR and VDS , while the simple expression of GSTM 1 is sufficient, possibly by a direct drug/protein interaction, to confer resistance against VRB .