Telomere dysfunction increases cisplatin and ecteinascidin-743 sensitivity of melanoma cells.
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.
Biroccio
Annamaria
A
Experimental Chemotherapy Laboratory, Centro di Ricerca Sperimentale, Regina Elena Cancer Institute, Rome, Italy.
Gabellini
Chiara
C
Amodei
Sarah
S
Benassi
Barbara
B
Del Bufalo
Donatella
D
Elli
Raffaella
R
Antonelli
Anna
A
D'Incalci
Maurizio
M
Zupi
Gabriella
G
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
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D019098:Telomerase; D000077606:Trabectedin; D002945:Cisplatin