title: Collateral sensitivity to cold stress and differential BCL-2 family expression in new daunomycin-resistant lymphoblastoid cell lines.
abstract: The acquisition of a multidrug-resistant (MDR) phenotype by tumor cells is one of the main causes of chemotherapy failure in cancer, and, usually, is due to the increased expression of P-glycoprotein (MDR-1, P-gp, ABCB1), a pump that expels chemotherapeutics from the cell and/or regulates apoptosis. Thus, it is fundamental to find drugs or stress stimuli with a capacity to induce apoptosis in such cells and to identify the mechanisms involved. We address this matter in human cells and establish new daunomycin (DNM)-resistant cell lines (IM-9R) by exposing the parental lymphoblastic cells (IM-9) to increasing doses of the anti-neoplastic drug, daunomycin. The resistance level of IM-9R cell lines, MDR-1 expression and functionality, collateral sensitivity and Bcl-2 and caspases protein expression are analyzed. As a result, we show for the first time that, unlike the parental cells, human lymphoblastic resistant cells exhibit collateral sensitivity to cold stress, confirming that this phenomenon is not exclusive to murine leukemic cells, but a broader one associated with the acquisition of drug resistance. Furthermore, the new resistant cell lines undergo a significant increase in active caspase-3 and -9 levels and drastic changes in Bcl-2 family protein expression during the process of MDR phenotype acquisition.
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.affiliation: Department of Biochemistry and Molecular Biology B and Immunology, University of Murcia, Murcia, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Cánovas
authors.affiliation: Department of Biochemistry and Molecular Biology B and Immunology, University of Murcia, Murcia, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: García-Peñarrubia
authors.affiliation: Department of Biochemistry and Molecular Biology B and Immunology, University of Murcia, Murcia, Spain. Electronic address: emartin@um.es.
authors.forename: Elena
authors.initials: E
authors.lastname: Martín-Orozco
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D003080:Cold Temperature; D003630:Daunorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013312:Stress, Physiological; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D019253:Proto-Oncogene Proteins c-bcl-2; D003630:Daunorubicin
keywords: Bcl-2; Caspases; Collateral sensitivity; Human lymphoblastic IM-9 cells; MDR; P-glycoprotein