title: Telomere dysfunction increases cisplatin and ecteinascidin-743 sensitivity of melanoma cells.
abstract: The aim of this study was to investigate the role of telomerase function on the chemosensitivity of melanoma cells. To this end, ecteinascidin-743 (ET-743) and cisplatin [cis-diamminedichloroplatinum(II) (CDDP)], two DNA-interacting drugs that invariably cause an arrest in the G(2)/M phase, and 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid (LND), a mitochondria-targeting drug inducing a G(1) block, were used. As experimental model, human melanoma clones showing reduced human telomerase reverse transcriptase (hTERT) expression and telomerase activity and characterized by telomere dysfunction were used. Reconstitution of telomerase activity by exogenous hTERT expression improved telomere function and reduced the sensitivity to CDDP and ET-743 without affecting LND susceptibility. The decreased sensitivity to CDDP and ET-743 was mainly caused by the ability of cells to recover from drug-induced damage, evaluated in terms of both chromosomal lesions and cell survival. The ability of hTERT-reconstituted cells to recover from drug-induced damage was attributable to the restoration of cell cycle progression. In fact, the cells without hTERT restoration remained for a prolonged time in the G(2)/M phase, and this cell cycle alteration made irreversible the drug-induced S-G(2)/M block and led to the activation of apoptotic program. On the contrary, the hTERT-reconstituted cells progressed quickly through the cell cycle, thus acquiring the capacity to recover from drug-induced block and to protect themselves from the G(2)/M phase-specific drug-triggered apoptosis.
authors.affiliation: Experimental Chemotherapy Laboratory, Centro di Ricerca Sperimentale, Regina Elena Cancer Institute, Rome, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Biroccio
authors.forename: Chiara
authors.initials: C
authors.lastname: Gabellini
authors.forename: Sarah
authors.initials: S
authors.lastname: Amodei
authors.forename: Barbara
authors.initials: B
authors.lastname: Benassi
authors.forename: Donatella
authors.initials: D
authors.lastname: Del Bufalo
authors.forename: Raffaella
authors.initials: R
authors.lastname: Elli
authors.forename: Anna
authors.initials: A
authors.lastname: Antonelli
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
authors.forename: Gabriella
authors.initials: G
authors.lastname: Zupi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage; D004268:DNA-Binding Proteins; D004149:Dioxoles / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D008545:Melanoma / Q000473:pathology; D008938:Mitosis / Q000187:drug effects; D019098:Telomerase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000502:physiology*; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D019098:Telomerase; D000077606:Trabectedin; D002945:Cisplatin