title: Doxorubicin and vinorelbine act independently via p53 expression and p38 activation respectively in breast cancer cell lines.
abstract: In the treatment of breast cancer, combination chemotherapy is used to overcome drug resistance. Combining doxorubicin and vinorelbine in the treatment of patients with metastatic breast cancer has shown high response rates; even single-agent vinorelbine in patients previously exposed to anthracyclines results in significant remission. Alterations in protein kinase-mediated signal transduction and p53 mutations may play a role in drug resistance with cross-talk between signal transduction and p53 pathways. The aim of this study was to establish the effects of doxorubicin and vinorelbine, as single agents, in combination, and as sequential treatments, on signal transduction and p53 in the breast cancer cell lines MCF-7 and MDA-MB-468. In both cell lines, increased p38 activity was demonstrated following vinorelbine but not doxorubicin treatment, whether vinorelbine was given prior to or simultaneously with doxorubicin. Mitogen-activated protein kinase (MAPK) activity and p53 expression remained unchanged following vinorelbine treatment. Doxorubicin treatment resulted in increased p53 expression, without changes in MAPK or p38 activity. These findings suggest that the effect of doxorubicin and vinorelbine used in combination may be achieved at least in part through distinct mechanisms. This additivism, where doxorubicin acts via p53 expression and vinorelbine through p38 activation, may contribute to the high clinical response rate when the two drugs are used together in the treatment of breast cancer.
authors.affiliation: Department of Surgery, University of Dundee, Dundee, UK.
authors.forename: A A
authors.initials: AA
authors.lastname: Liem
authors.forename: M V C L
authors.initials: MV
authors.lastname: Appleyard
authors.forename: M A
authors.initials: MA
authors.lastname: O'Neill
authors.forename: T R
authors.initials: TR
authors.lastname: Hupp
authors.forename: M P
authors.initials: MP
authors.lastname: Chamberlain
authors.forename: A M
authors.initials: AM
authors.lastname: Thompson
mesh_terms: D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D016158:Genes, p53 / Q000187:drug effects*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000077235:Vinorelbine; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D016159:Tumor Suppressor Protein p53; D014747:Vinblastine; D004317:Doxorubicin; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000077235:Vinorelbine