title: Differential involvement of glutathione S-transferase mu 1 and multidrug resistance protein 1 in melanoma acquired resistance to vinca alkaloids.
abstract: 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 (GSTM1) acts in synergy with multidrug resistance protein 1 (MRP1) to protect GSTM1-transfected human CAL1 melanoma cells from toxic effects of vincristine (VCR). Herein, we investigated the role of these proteins in the acquired resistance of CAL1 cells to vinca alkaloids (VAs). Resistant lines were established by continuous exposure (>1 year) of parental CAL1-wt cells to VCR, vindesine (VDS), or vinorelbine (VRB): CAL1R-VCR, CAL1R-VDS, CAL1R-VRB, respectively. All resistant lines displayed more than 10-fold increase in resistance to their selection VA, and specifically expressed GSTM1. Suggesting a direct interaction between this protein and VAs, each VA specifically decreased the GSTM1-mediated glutathione conjugation activity in cell lysates. Curcumin (GSTM1 inhibitor), BSO (glutathione synthesis inhibitor), and MK571 (MRP1 inhibitor) considerably reversed the acquired resistance to VCR and VDS, but not to VRB. Microarray data analysis revealed similar gene expression patterns of CAL1R-VCR and CAL1R-VDS, and a distinct one for CAL1R-VRB. These data suggest a differential involvement of GSTM1 and MRP1 in acquired resistance to VAs. A coordinated expression and activity of GSTM1 and MRP1 is required to protect CAL1 cells from VCR and VDS, while the simple expression of GSTM1 is sufficient, possibly by a direct drug/protein interaction, to confer resistance against VRB.
authors.affiliation: Laboratoire de Toxicologie du Médicament, Institut des Biomolécules Max Mousseron (UMR5247), UFR des Sciences Pharmaceutiques et Biologiques, Université Montpellier I, 15 avenue Charles Flahault, BP14491, Montpellier, 34093, France.
authors.forename: Chaker
authors.initials: C
authors.lastname: Attaoua
authors.forename: Laure-Anaïs
authors.initials: LA
authors.lastname: Vincent
authors.forename: Aida
authors.initials: A
authors.lastname: Abdel Jaoued
authors.forename: Kamel
authors.initials: K
authors.lastname: Hadj-Kaddour
authors.forename: Qiang
authors.initials: Q
authors.lastname: Baï
authors.forename: John
authors.initials: J
authors.lastname: De Vos
authors.forename: Laurence
authors.initials: L
authors.lastname: Vian
authors.forename: Pierre
authors.initials: P
authors.lastname: Cuq
mesh_terms: D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000031:analogs & derivatives / Q000494:pharmacology; D014748:Vinca Alkaloids / Q000494:pharmacology*; D014751:Vindesine / Q000494:pharmacology; D000077235:Vinorelbine
chemical_list: D005982:Glutathione Transferase; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014747:Vinblastine; D014748:Vinca Alkaloids; D014751:Vindesine; D000077235:Vinorelbine; C421109:multidrug resistance-associated protein 1
keywords: glutathione S-transferases; melanoma; multidrug resistance proteins; vinca alkaloids