cDNA microarray analysis of multidrug resistance: doxorubicin selection produces multiple defects in apoptosis signaling pathways.

TitlecDNA microarray analysis of multidrug resistance: doxorubicin selection produces multiple defects in apoptosis signaling pathways.
Publication TypeJournal Article
Year of Publication2001
AuthorsWatts GS, Futscher BW, Isett R, Gleason-Guzman M, Kunkel MW, Salmon SE
JournalJ Pharmacol Exp Ther
Date Published2001 Nov
KeywordsAntibiotics, Antineoplastic, Apoptosis, Carcinogens, DNA, DNA, Neoplasm, Doxorubicin, Drug Resistance, Multiple, Drug Resistance, Neoplasm, Humans, Oligonucleotide Array Sequence Analysis, Phenotype, Signal Transduction, Staurosporine, Tumor Cells, Cultured

Doxorubicin plays an important role in the treatment of leukemias, lymphomas, and a variety of carcinomas. Tumor cell resistance to doxorubicin is often associated with expression of the multidrug resistance gene MDR1, which codes for the drug efflux pump P-glycoprotein, and a multidrug-resistant phenotype. Evidence from multiple sources suggests, however, that additional genes besides MDR1 are involved in development of multidrug resistance. To identify genes involved in the multidrug resistance phenotype, we created a 5760-gene cDNA microarray to search for differentially expressed genes between the human multiple myeloma cell line RPMI 8226 and its doxorubicin-selected sublines 8226/Dox6 and 8226/Dox40, both of which express MDR1 and are multidrug-resistant. The cDNA microarray results identified a set of differentially expressed genes, which included MDR1 as expected. Thirty Northern analyses were used to confirm the results of the cDNA microarrays; comparison with the microarray results showed a 90% agreement between the two techniques. Within the set of differentially expressed genes identified by the cDNA microarrays, 29 were of particular interest as they can participate in apoptotic signaling, particularly as mediated by ceramide and the mitochondrial permeability transition. The functional importance of these changes in gene expression is supported by their explanation of the 8226/Dox cell lines' cross-resistance to substances that are not P-glycoprotein substrates, such as Fas/CD95 ligand and staurosporine. We conclude that doxorubicin selection led to changes in gene expression that reduce the apoptotic response to death-inducing stimuli and thus contribute to the multidrug resistance phenotype.

Alternate JournalJ. Pharmacol. Exp. Ther.
PubMed ID11602652
Grant ListP30 CA023074 / CA / NCI NIH HHS / United States
3P30CA23074-19 / CA / NCI NIH HHS / United States
CA65662 / CA / NCI NIH HHS / United States
T32 CA 09213 / CA / NCI NIH HHS / United States