Gene expression profiling of epothilone A-resistant cells.
In the current study, we isolated sublines of the human breast adenocarcinoma cell line MDA 435 that exhibited increasing resistance to epothilone A, a microtubule-stabilizing cytotoxic agent. The resistant cells did not express P glycoprotein or multidrug resistance-associated protein (MRP) which are known mediators of multidrug resistance (MDR). Two groups of epothilone A-resistant cells were selected: cells which exhibited low resistance to both epothilone A and Taxol, and cells which exhibit low resistance to Taxol but high resistance to epothilone A. cDNA microarrays of epothilone A-resistant and Taxol-resistant cells were utilized to further characterize epothilone A resistance. Hierarchical clustering of genes according to their levels of expression indicated that the majority of genes which were highly expressed in epothilone A-resistant cells but not in taxol-resistant MDR cells encode known interferon-inducible proteins. Genes whose expression increased with increasing epothilone A resistance include microtubule-associated GTPases, cytoskeletal proteins, cell signalling proteins and a drug metabolising enzyme. The majority of the genes that were repressed in both epothilone A- and Taxol-resistant cells encode proteins regulating cellular growth signalling mechanisms.
Atadja
Peter
P
Functional Genomics, Novartis Corporation, Summit, NJ 07901, USA.
Yan-Neale
Yan
Y
Towbin
Harry
H
Buxton
Frank
F
Cohen
Dalia
D
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D034261:Epothilones / Q000494:pharmacology*; D005260:Female; D020558:GTP Phosphohydrolases / Q000096:biosynthesis / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006133:Growth Substances / Q000096:biosynthesis / Q000235:genetics; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D007372:Interferons / Q000494:pharmacology; D008297:Male; D008870:Microtubules / Q000187:drug effects; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D017239:Paclitaxel / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D003598:Cytoskeletal Proteins; D034261:Epothilones; D006133:Growth Substances; D009363:Neoplasm Proteins; C093787:epothilone A; D007372:Interferons; D020558:GTP Phosphohydrolases; D017239:Paclitaxel; C093788:epothilone B