title: Diphenyl ditelluride-induced cell cycle arrest and apoptosis: a relation with topoisomerase I inhibition.
abstract: The diphenyl ditelluride (DPDT) is a prototype for the development of new biologically active molecules. In previous studies, DPDT showed an elevated cytotoxicity in Chinese hamster fibroblast (V79) cells but the mechanisms for reduction of cell viability still remain unknown. DPDT showed mutagenic properties by induction of frameshift mutations in bacterium Salmonella typhimurium and yeast Saccharomyces cerevisiae. This organotelluride also induced DNA strand breaks in V79 cells. In this work, we investigated the mechanism of DPDT cytotoxicity by evaluating the effects of this compound on cell cycle progression, apoptosis induction and topoisomerase I inhibition. Significant decrease of V79 cell viability after DPDT treatment was revealed by MTT assay. Morphological analysis showed induction of apoptosis and necrosis by DPDT in V79 cells. An increase of caspase 3/7 activity confirmed apoptosis induction. The cell cycle analysis showed an increase in the percentage of V79 cells in S phase and sub-G1 phase. The yeast strain deficient in topoisomerase I (Topo I) showed higher tolerance to DPDT compared with the isogenic wild-type strain, suggesting that the interaction with this enzyme could be involved in DPDT toxicity. The sensitivity to DPDT found in top3∆ strain indicates that yeast topoisomerase 3 (Top3p) could participate in the repair of DNA lesions induced by the DPDT. We also demonstrated that DPDT inhibits human DNA topoisomerase I (Topo I) activity by DNA relaxation assay. Therefore, our results suggest that the DPDT-induced cell cycle arrest and reduction in cell viability could be attributed to interaction with topoisomerase I enzyme.
authors.affiliation: Department of Biophysics, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
authors.forename: Patrícia M
authors.initials: PM
authors.lastname: Jorge
authors.forename: Iuri M
authors.initials: IM
authors.lastname: de Oliveira
authors.forename: Eduardo C
authors.initials: EC
authors.lastname: Filippi Chiela
authors.forename: Cassiana M
authors.initials: CM
authors.lastname: Viau
authors.forename: Jenifer
authors.initials: J
authors.lastname: Saffi
authors.forename: Fabiana
authors.initials: F
authors.lastname: Horn
authors.forename: Renato M
authors.initials: RM
authors.lastname: Rosa
authors.forename: Temenouga N
authors.initials: TN
authors.lastname: Guecheva
authors.forename: João A
authors.initials: JA
authors.lastname: Pêgas Henriques
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001555:Benzene Derivatives / Q000633:toxicity*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009336:Necrosis / Q000139:chemically induced; D009942:Organometallic Compounds / Q000633:toxicity*; D012441:Saccharomyces cerevisiae / Q000187:drug effects; D059004:Topoisomerase I Inhibitors / Q000633:toxicity*
chemical_list: D001555:Benzene Derivatives; D009942:Organometallic Compounds; D059004:Topoisomerase I Inhibitors; C434247:diphenylditelluride; D053148:Caspase 3; D053179:Caspase 7