Cited by 262Isoquinoline Alkaloid SynthesisCancer therapeutics and mechanismsBioactive Compounds and Antitumor Agents

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Ecteinascidin-743 (ET-743), a natural marine compound, with a unique mechanism of action

Erba, E, Bergamaschi, D, Bassano, L, Damia, G, Ronzoni, S, Faircloth, G.T, D'Incalci, M·2001·European Journal of Cancer

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Abstract

The mode of action of Ecteinascidin-743 (ET-743), a marine tetrahydroisoquinoline alkaloid isolated from Ecteinascidia turbinata, which has shown very potent antitumour activity in preclinical systems and encouraging results in Phase I clinical trials was investigated at a cellular level. Both SW620 and LoVo human intestinal carcinoma cell lines exposed for 1 h to ET-743 progress through S phase more slowly than control cells and then accumulate in the G2M phase. The sensitivity to ET-743 of G1 synchronised cells was much higher than that of cells synchronised in S phase and even higher than that of cells synchronised in G2M. ET-743 concentrations up to four times higher than the IC(50) value caused no detectable DNA breaks or DNA-protein cross-links as assessed by alkaline elution techniques. ET-743 induced a significant increase in p53 levels in cell lines expressing wild-type (wt) (p53). However, the p53 status does not appear to be related to the ET-743 cytotoxic activity as demonstrated by comparing the drug sensitivity in p53 (-/-) or (+/+) mouse embryo fibroblasts and in A2780 ovarian cancer cells or the A2780/CX3 sub-line transfected with a dominant-negative mutant TP53. The cytotoxic potency of ET-743 was comparatively evaluated in CHO cell lines proficient or deficient in nucleotide excision repair (NER), and it was found that ET-743 was approximately 7-8 times less active in ERCC3/XPB and ERCC1-deficient cells than control cells. The findings that G1 phase cells are hypersensitive and that NER-deficient cells are resistant to ET-743 indicate that the mode of action of ET-743 is unique and different from that of other DNA-interacting drugs.

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Authors: Erba, E., Bergamaschi, D., Bassano, L., Damia, G., Ronzoni, S., Faircloth, G. T., & D'Incalci, M.
Affiliations: Mario Negri Institute for Pharmacological Research (IT)
Rayonix (United States) (US)
Corresponding author: Erba, E
ORCID: Bergamaschi, D
Damia, G
Ronzoni, S
Venue: European Journal of Cancer
Publisher: Elsevier BV
Published: 2001-01
Volume: 37
Issue: 1
Pages: 97-105
ISSN: 0959-8049 (ISSN-L)
DOI: 10.1016/s0959-8049(00)00357-9
OpenAlex: W2153737617
Cited by: 262
References: 28
Citations by year: 2026: 4 · 2025: 4 · 2024: 7 · 2023: 7 · 2022: 8 · 2021: 7 · 2020: 6 · 2019: 6 · 2018: 6 · 2017: 8 · 2016: 10 · 2015: 21 · 2014: 19 · 2013: 9 · 2012: 4
FWCI: 6.19
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: European Journal of Cancer (publishedVersion)
PubMed (publishedVersion)
Funders: Cancer Research Institute
Associazione Italiana per la Ricerca sul Cancro
Topics: Physical Sciences › Chemistry › Organic Chemistry › Isoquinoline Alkaloid Synthesis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
Keywords: trabectedin, Ecteinascidia turbinata, cell cycle arrest, p53, nucleotide excision repair, ERCC1, DNA damage, DNA-protein crosslinks, ovarian cancer cell lines, drug resistance
MeSH terms: Trabectedin, Cell Cycle, Cell Division, Colonic Neoplasms, Dioxoles, DNA Damage, DNA, Neoplasm, Drug Screening Assays, Antitumor, Humans, Isoquinolines, Tumor Cells, Cultured, Tumor Suppressor Protein p53, Cyclins, Antineoplastic Agents, Alkylating, Tetrahydroisoquinolines

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Ecteinascidin-743 (ET-743), a natural marine compound, with a unique mechanism of action

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