title: Acquisition of MDR phenotype by leukemic cells is associated with increased caspase-3 activity and a collateral sensitivity to cold stress.
abstract: The acquisition of a multidrug-resistant (MDR) phenotype by tumor cells that renders them unsusceptible to anti-neoplasic agents is one of the main causes of chemotherapy failure in human malignancies. The increased expression of P-glycoprotein (MDR1, P-gp, ABCB1) in tumor cells contributes to drug resistance by extruding chemotherapeutic agents or by regulating programmed cell death. In a study of MDR cell survival under cold stress conditions, it was found that resistant leukemic cells with P-gp over-expression, but not their sensitive counterparts, are hypersensitive to cold-induced cell death when exposed to temperatures below 4 °C. The transfection of parental cells with a P-gp-expressing plasmid makes these cells sensitive to cold stress, demonstrating an association between P-gp expression and cell death at low temperatures. Furthermore, we observed increased basal expression and activity of effector caspase-3 at physiological temperature (37 °C) in MDR cells compared with their parental cell line. Treatment with a caspase-3 inhibitor partially rescues MDR leukemic cells from cold-induced apoptosis, which suggests that the cell death mechanism may require caspase-3 activity. Taken together, these findings demonstrate that P-gp expression plays a role in MDR cell survival, and is accompanied by a collateral sensitivity to death induced by cold stress. These findings may assist in the design of specific therapeutic strategies to complement current chemotherapy treatment against cancer.
authors.affiliation: Department of Biochemistry and Molecular Biology B and Immunology, University of Murcia, Murcia, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Cerezo
authors.forename: Miriam
authors.initials: M
authors.lastname: Lencina
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Ruiz-Alcaraz
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Ferragut
authors.forename: Miguel
authors.initials: M
authors.lastname: Saceda
authors.forename: Manuel
authors.initials: M
authors.lastname: Sanchez
authors.forename: Manuel
authors.initials: M
authors.lastname: Cánovas
authors.forename: Pilar
authors.initials: P
authors.lastname: García-Peñarrubia
authors.forename: Elena
authors.initials: E
authors.lastname: Martín-Orozco
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism*; D016923:Cell Death; D045744:Cell Line, Tumor; D003080:Cold Temperature; D018432:Drug Resistance, Multiple; D007939:Leukemia L1210 / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D010718:Phosphatidylserines / Q000378:metabolism; D013312:Stress, Physiological
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D010718:Phosphatidylserines; D053148:Caspase 3