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

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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.