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RESEARCH PRODUCT
Factors Determining Sensitivity and Resistance of Tumor Cells to Arsenic Trioxide
Judith BauerThomas EfferthThomas EfferthMargaret M. BriehlSerkan SertelKai HockMargaret E. TomePeter K. Plinkertsubject
MicroarraysTumor PhysiologyCancer Treatmentlcsh:MedicineToxicologyArsenicalschemistry.chemical_compoundArsenic TrioxideBasic Cancer ResearchRNA NeoplasmArsenic trioxidelcsh:ScienceOligonucleotide Array Sequence AnalysisMultidisciplinaryintegumentary systemCytotoxinsOxidesTransfectionNeoplasm ProteinsGene Expression Regulation NeoplasticActin CytoskeletonOncologyMedicineThioredoxinSignal TransductionResearch Articleinorganic chemicalsAcute promyelocytic leukemiaToxic Agentschemistry.chemical_elementAntineoplastic AgentsBiologyComplementary and Alternative MedicineCell Line TumormedicineHumansRNA MessengerBiologyArseniclcsh:RComputational BiologyCancers and Neoplasmsmedicine.diseaseActin cytoskeletonMolecular biologychemistryDrug Resistance NeoplasmApoptosisCell culturelcsh:Qdescription
Previously, arsenic trioxide showed impressive regression rates of acute promyelocytic leukemia. Here, we investigated molecular determinants of sensitivity and resistance of cell lines of different tumor types towards arsenic trioxide. Arsenic trioxide was the most cytotoxic compound among 8 arsenicals investigated in the NCI cell line panel. We correlated transcriptome-wide microarray-based mRNA expression to the IC(50) values for arsenic trioxide by bioinformatic approaches (COMPARE and hierarchical cluster analyses, Ingenuity signaling pathway analysis). Among the identified pathways were signaling routes for p53, integrin-linked kinase, and actin cytoskeleton. Genes from these pathways significantly predicted cellular response to arsenic trioxide. Then, we analyzed whether classical drug resistance factors may also play a role for arsenic trioxide. Cell lines transfected with cDNAs for catalase, thioredoxin, or the anti-apoptotic bcl-2 gene were more resistant to arsenic trioxide than mock vector transfected cells. Multidrug-resistant cells overexpressing the MDR1, MRP1 or BCRP genes were not cross-resistant to arsenic trioxide. Our approach revealed that response of tumor cells towards arsenic trioxide is multi-factorial.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2012-01-13 | PLoS ONE |