title: A Novel Inhibitor of Topoisomerase I Is Selectively Toxic for a Subset of Non-Small Cell Lung Cancer Cell Lines.
abstract: SW044248, identified through a screen for chemicals that are selectively toxic for non-small cell lung cancer (NSCLC) cell lines, was found to rapidly inhibit macromolecular synthesis in sensitive, but not in insensitive, cells. SW044248 killed approximately 15% of a panel of 74 NSCLC cell lines and was nontoxic to immortalized human bronchial cell lines. The acute transcriptional response to SW044248 in sensitive HCC4017 cells correlated significantly with inhibitors of topoisomerases and SW044248 inhibited topoisomerase 1 (Top1) but not topoisomerase 2. SW044248 inhibited Top1 differently from camptothecin and camptothecin did not show the same selective toxicity as SW044248. Elimination of Top1 by siRNA partially protected cells from SW044248, although removing Top1 was itself eventually toxic. Cells resistant to SW044248 responded to the compound by upregulating CDKN1A and siRNA to CDKN1A sensitized those cells to SW044248. Thus, at least part of the differential sensitivity of NSCLC cells to SW044248 is the ability to upregulate CDKN1A.
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Iryna O
authors.initials: IO
authors.lastname: Zubovych
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Anirudh
authors.initials: A
authors.lastname: Sethi
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Aditya
authors.initials: A
authors.lastname: Kulkarni
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Vural
authors.initials: V
authors.lastname: Tagal
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas. michael.roth@utsouthwestern.edu.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Roth
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms; D014176:Protein Biosynthesis / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects; D059004:Topoisomerase I Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007211:Indoles; C585392:SW044248; D059004:Topoisomerase I Inhibitors; D014157:Transcription Factors; D014227:Triazines; C101003:ELF2 protein, human