title: Factors determining sensitivity and resistance of tumor cells to arsenic trioxide.
abstract: 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.
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Serkan
authors.initials: S
authors.lastname: Sertel
authors.forename: Margaret
authors.initials: M
authors.lastname: Tome
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Briehl
authors.forename: Judith
authors.initials: J
authors.lastname: Bauer
authors.forename: Kai
authors.initials: K
authors.lastname: Hock
authors.forename: Peter K
authors.initials: PK
authors.lastname: Plinkert
authors.forename: Thomas
authors.initials: T
authors.lastname: Efferth
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis; D020411:Oligonucleotide Array Sequence Analysis; D010087:Oxides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D003603:Cytotoxins; D009363:Neoplasm Proteins; D010087:Oxides; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000077237:Arsenic Trioxide