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Differential involvement of glutathione S‐transferase mu 1 and multidrug resistance protein 1 in melanoma acquired resistance to vinca alkaloids
Author(s) -
Attaoua Chaker,
Vincent LaureAnaïs,
Abdel Jaoued Aida,
HadjKaddour Kamel,
Baï Qiang,
De Vos John,
Vian Laurence,
Cuq Pierre
Publication year - 2015
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/fcp.12093
Subject(s) - vinca , multidrug resistance associated proteins , glutathione , vincristine , buthionine sulfoximine , multiple drug resistance , biology , pharmacology , microbiology and biotechnology , drug resistance , glutathione s transferase , melanoma , cancer research , gene , biochemistry , chemotherapy , enzyme , atp binding cassette transporter , genetics , transporter , cyclophosphamide
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 .