title: 5-FdUrd-araC heterodinucleoside re-establishes sensitivity in 5-FdUrd- and AraC-resistant MCF-7 breast cancer cells overexpressing ErbB2.
abstract: ErbB2 overexpressing breast tumors have a poor prognosis and a high risk to develop chemoresistance to therapeutic treatment. "Chemoresistance" is a response of cells to toxic stress, and, although it is a common phenomenon, it is still poorly defined. However, a detailed understanding is required to target desensitized pathways and mechanisms for successful reactivation as part of a tailored therapy. To gain insight, which malfunctions contribute to chemoresistance, two mechanisms relevant for tissue homeostasis, the regulation of the cell cycle and of apoptosis, were investigated. Maternal MCF-7- and ErbB2-overexpressing MCF-7(erbB2) breast cancer cells were long term pretreated with 2'-deoxy-5-fluorodeoxyuridine (5-FdUrd) or 1-beta-d-arabinofuranosylcytosine (AraC) and the acquisition of drug-insensitivity was analyzed. A phosphate-conjugated heterodinucleoside consisting of one 5-FdUrd- and one AraC-moiety (5-fluoro-2'-desoxyuridylyl-(3'-->5')-Arabinocytidine) was utilized as a tool to assess the type of acquired resistances. ErbB2-overexpression disrupted proper cell cycle regulation and furthermore facilitated the development of an apoptosis-refractory phenotype upon exposure to 5-FdUrd. Experiments with dimer 5-FdUrd-araC in ErbB2-overexpressing MCF-7(erbB2) cells, and also with nucleoside 5-FdUrd in maternal MCF-7 cells, evidenced that the phenotypes of resistance to cell cycle inhibition and to apoptosis induction were differently affected. The expression profile of cyclin D1 (but not that of p53, p21, or p27) correlated with the proliferative phenotypes and nuclear accumulation of apoptosis inducing factor (but not activation of caspase 7) with apoptotic phenotypes. Dimer 5-FdUrd-araC overrode acquired chemoresistances, whereas combined application of 5-FdUrd and AraC exhibited significantly less activity. Dimer 5-FdUrd-araC remained active in MCF-7 clones most likely by circumventing the prerequisite of first-step phosphorylation. The acquisition of chemoresistance encompassed the affection of apoptosis- and cell-cycle regulation to, respectively, different extents. Thus, drug-induced cell cycle arrest and apoptosis induction are independent of each other.
authors.affiliation: Institute of Clinical Pathology, Medical University of Vienna, A-1090 Vienna, Austria.
authors.forename: Stephen
authors.initials: S
authors.lastname: Strasser
authors.forename: Susanne
authors.initials: S
authors.lastname: Maier
authors.forename: Christina
authors.initials: C
authors.lastname: Leisser
authors.forename: Philipp
authors.initials: P
authors.lastname: Saiko
authors.forename: Sibylle
authors.initials: S
authors.lastname: Madlener
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Bader
authors.forename: Astrid
authors.initials: A
authors.lastname: Bernhaus
authors.forename: Marieta
authors.initials: M
authors.lastname: Gueorguieva
authors.forename: Susanne
authors.initials: S
authors.lastname: Richter
authors.forename: Robert M
authors.initials: RM
authors.lastname: Mader
authors.forename: Jozefa
authors.initials: J
authors.lastname: Wesierska-Gadek
authors.forename: Herbert
authors.initials: H
authors.lastname: Schott
authors.forename: Thomas
authors.initials: T
authors.lastname: Szekeres
authors.forename: Monika
authors.initials: M
authors.lastname: Fritzer-Szekeres
authors.forename: Georg
authors.initials: G
authors.lastname: Krupitza
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D019281:Dimerization; D019008:Drug Resistance, Neoplasm; D005260:Female; D005467:Floxuridine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000964:Antimetabolites, Antineoplastic; D053179:Caspase 7; D019938:Cyclin D1; D003561:Cytarabine; D005467:Floxuridine; D018719:Erb-b2 Receptor Tyrosine Kinases; C517379:5-fluoro-2'-deoxyuridylyl-(3'-5')-arabinocytidine