Unique pattern of ET-743 activity in different cellular systems with defined deficiencies in DNA-repair pathways

Giovanna Damia, Simonetta Silvestri, Laura Carrassa, Laura Filiberti, Glynn T. Faircloth, Giordano Liberi, Marco Foiani, Maurizio D'Incalci

Research output: Contribution to journalArticle

Abstract

The cytotoxic activity of ecteinascidin 743 (ET-743), a natural product derived from the marine tunicate Ecteinascidia turbinata that exhibits potent anti-tumor activity in pre-clinical systems and promising activity in phase I and II clinical trials, was investigated in a number of cell systems with well-defined deficiencies in DNA-repair mechanisms. ET-743 binds to N2 of guanine in the minor groove, but its activity does not appear to be related to DNA-topoisomerase I poisoning as the drug is equally active in wild-type yeast and in yeast with a deletion in the DNA-topoisomerase I gene. Defects in the mismatch repair pathway, usually associated with increased resistance to methylating agents and cisplatin, did not affect the cytotoxic activity of ET-743. However, ET-743 did show decreased activity (from 2- to 8-fold) in nucleotide excision repair (NER)-deficient cell lines compared to NER-proficient cell lines, from either hamsters or humans. Restoration of NER function sensitized cells to ET-743 treatment. The DNA double-strand-break repair pathway was also investigated using human glioblastoma cell lines MO59K and MO59J, respectively, proficient and deficient in DNA-dependent protein kinase (DNA-PK). ET-743 was more effective in cells lacking DNA-PK; moreover, pre-treatment of HCT-116 colon carcinoma cells with wortmannin, a potent inhibitor of DNA-PK, sensitized cells to ET-743. An increase in ET-743 sensitivity was also observed in ataxia telangiectasia-mutated cells. Our data strongly suggest that ET-743 has a unique mechanism of interaction with DNA.

Original languageEnglish
Pages (from-to)583-588
Number of pages6
JournalInternational Journal of Cancer
Volume92
Issue number4
DOIs
Publication statusPublished - May 15 2001

Keywords

  • ATM
  • DNA repair
  • DNA-protein kinase
  • ET-743
  • Marine compound
  • Nucleotide excision repair

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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