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 language | English |
|---|---|
| Pages (from-to) | 583-588 |
| Number of pages | 6 |
| Journal | International Journal of Cancer |
| Volume | 92 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - May 15 2001 |
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Keywords
- ATM
- DNA repair
- DNA-protein kinase
- ET-743
- Marine compound
- Nucleotide excision repair
ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Unique pattern of ET-743 activity in different cellular systems with defined deficiencies in DNA-repair pathways. / Damia, Giovanna; Silvestri, Simonetta; Carrassa, Laura; Filiberti, Laura; Faircloth, Glynn T.; Liberi, Giordano; Foiani, Marco; D'Incalci, Maurizio.
In: International Journal of Cancer, Vol. 92, No. 4, 15.05.2001, p. 583-588.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Unique pattern of ET-743 activity in different cellular systems with defined deficiencies in DNA-repair pathways
AU - Damia, Giovanna
AU - Silvestri, Simonetta
AU - Carrassa, Laura
AU - Filiberti, Laura
AU - Faircloth, Glynn T.
AU - Liberi, Giordano
AU - Foiani, Marco
AU - D'Incalci, Maurizio
PY - 2001/5/15
Y1 - 2001/5/15
N2 - 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.
AB - 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.
KW - ATM
KW - DNA repair
KW - DNA-protein kinase
KW - ET-743
KW - Marine compound
KW - Nucleotide excision repair
UR - http://www.scopus.com/inward/record.url?scp=0035874074&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035874074&partnerID=8YFLogxK
U2 - 10.1002/ijc.1221
DO - 10.1002/ijc.1221
M3 - Article
C2 - 11304695
AN - SCOPUS:0035874074
VL - 92
SP - 583
EP - 588
JO - International Journal of Cancer
JF - International Journal of Cancer
SN - 0020-7136
IS - 4
ER -