Inhibition of telomerase activity by a distamycin derivative: Effects on cell proliferation and induction of apoptosis in human cancer cells

N. Zaffaroni, S. Lualdi, R. Villa, D. Bellarosa, C. Cermele, P. Felicetti, C. Rossi, L. Orlandi, M. G. Daidone

Research output: Contribution to journalArticlepeer-review

Abstract

In this study, we evaluated the potential of the distamycin derivative MEN 10716 as a telomerase inhibitor. Exposure of human melanoma cell extracts to MEN 10716 induced a dose-dependent inhibition of telomerase activity, with an IC50 of 24±3 μM. When intact JR8 melanoma cells were chronically exposed to the drug (200 μM every other day for 50 days), a marked inhibition (>80%) of the enzyme's catalytic activity was consistently observed starting from day 1. At later points in time, MEN 10716 inhibited melanoma cell proliferation and induced apoptosis. Cells surviving MEN 10716 exposure were characterised by a higher melanin content and a greater expression of p16INK4A protein than control cells. The effects of MEN 10716 were subsequently evaluated in different tumour cell systems. In particular, even in the H460 non-small cell lung cancer cell line, chronic exposure of the cells to the drug (100 μM every other day for 50 days) induced a consistent inhibition (>85%) of telomerase activity, a reduction of cell proliferation potential, and apoptosis. Conversely, MEN 10716 treatment did not appreciably inhibit cell proliferation in the U2-OS telomerase-negative human osteogenic sarcoma cell line. Interestingly, no variation in the mean telomere length was observed in MEN 10716-treated JR8 melanoma cells, whereas an appreciable increase in the mean telomere length was found in H460 lung cancer cells after drug exposure. Overall, the results of the study indicate that MEN 10716 is a possible telomerase inhibitor and suggest that abrogation of telomerase activity can affect cell proliferation even through pathways that are not dependent on telomere erosion.

Original languageEnglish
Pages (from-to)1792-1801
Number of pages10
JournalEuropean Journal of Cancer
Volume38
Issue number13
DOIs
Publication statusPublished - 2002

Keywords

  • Apoptosis
  • Distamycin derivative
  • Melanoma
  • Non-small cell lung carcinoma
  • Osteogenic sarcoma
  • Telomerase
  • Telomere

ASJC Scopus subject areas

  • Cancer Research
  • Hematology
  • Oncology

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