Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair

Takebayashi, Yuji; Pourquier, Philippe; Zimonjic, Drazen B.; Nakayama, Kentaro; Emmert, Steffen; Ueda, Takahiro; Urasaki, Yoshimasa; Kanzaki, Atsuko; Akiyama, Shin–ichi; Popescu, Nicholas C.; Kraemer, Kenneth H.; Pommier, ﻿Yves

doi:10.1038/91008

Cited by 323 publications

(290 citation statements)

References 33 publications

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“…The resistance to trabectedin of the colorectal carcinoma ER5 cell line (derived from the HCT116 cells) is associated with a loss of heterozygosity at 13q33, where the gene encoding for XPG is located. Sequential analysis of the XPG gene showed an insertion of adenine at codon 240, which resulted in a stop codon at position 243 (5,30). Another mechanism associated with trabectedin's resistance has been described in human surgically resected chondrosarcoma cells (CS-1; ref.…”

Section: Resistance To Trabectedinmentioning

confidence: 99%

A Review of Trabectedin (ET-743): A Unique Mechanism of Action

D’Incalci

Galmarini

2010

Molecular Cancer Therapeutics

381

291

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Trabectedin (ET-743) is a marine alkaloid isolated from the Caribbean tunicate Ecteinascidia turbinata, with a chemical structure characterized by three fused tetrahydroisoquinoline rings. Two of these rings (subunits A and B) provide the framework for covalent interaction with the minor groove of the DNA double helix, whereas the third ring (subunit C) protrudes from the DNA duplex, apparently allowing interactions with adjacent nuclear proteins. The compound's chemical interactions trigger a cascade of events that interfere with several transcription factors, DNA binding proteins, and DNA repair pathways, likely to be different from other DNA-interacting agents. Trabectedin also causes modulation of the production of cytokines and chemokines by tumor and normal cells, suggesting that the antitumor activity could also be ascribed to changes in the tumor microenvironment. The promising data on the combination of trabectedin with other anticancer agents, observed in preclinical systems, have prompted several clinical studies that are currently ongoing. One of these combinations (trabectedin-pegylated liposomal doxorubicin) was recently authorized by the European Commission for the treatment of patients with relapsed platinum-sensitive ovarian cancer.

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Section: Resistance To Trabectedinmentioning

confidence: 99%

A Review of Trabectedin (ET-743): A Unique Mechanism of Action

D’Incalci

Galmarini

2010

Molecular Cancer Therapeutics

381

291

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“…This type of interaction differs from that observed for other DNA-binding antitumor drugs and could account for some of the distinctive pharmacologic features of trabectedin, such as the potent and rapid inhibition of activated but not constitutive transcription (3,4) and the atypical response detected in cells with deficiencies in nucleotide excision repair (NER). In this latter respect, whereas all known DNA-interacting drugs are either more effective or equally effective in NERdeficient cells relative to their NER-proficient counterparts (5 -8), trabectedin is paradoxically less cytotoxic in NERdeficient cells (9 -12), particularly in those harboring a deleterious mutation in the XPG endonuclease (11,13). On the other hand, experimental evidence from different laboratories has shown that both yeast mutants with gene deletions in the RAD52 epistasis group [e.g., Saccharomyces cerevisiae rad52D (9) and Schizosaccharomyces pombe rad51D and rad54D cells (13,14)] and mammalian cells deficient in XRCC3, BRCA2, RAD51C, and XRCC2 (15) are much more sensitive to trabectedin than their normal counterparts.…”

Section: Introductionmentioning

confidence: 99%

Relevance of the Fanconi anemia pathway in the response of human cells to trabectedin

Casado

Rı́o

Marco³

et al. 2008

Molecular Cancer Therapeutics

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Trabectedin (Yondelis; ET-743) is a potent anticancer drug that binds to DNA by forming a covalent bond with a guanine in one strand and one or more hydrogen bonds with the opposite strand. Using a fluorescence-based melting assay, we show that one single trabectedin-DNA adduct increases the thermal stability of the double helix by >20°C. As deduced from the analysis of phosphorylated H2AX and Rad51 foci, we observed that clinically relevant doses of trabectedin induce the formation of DNA double-strand breaks in human cells and activate homologous recombination repair in a manner similar to that evoked by the DNA interstrand cross-linking agent mitomycin C (MMC). Because one important characteristic of this drug is its marked cytotoxicity on cells lacking a functional Fanconi anemia (FA) pathway, we compared the response of different subtypes of FA cells to MMC and trabectedin. Our data clearly show that human cells with mutations in FANCA, FANCC, FANCF, FANCG, or FANCD1 genes are highly sensitive to both MMC and trabectedin. However, in marked contrast to MMC, trabectedin does not induce any significant accumulation of FA cells in G 2 -M. The critical relevance of FA proteins in the response of human cells to trabectedin reported herein, together with observations showing the role of the FA pathway in cancer suppression, strongly suggest that screening for mutations in FA genes may facilitate the identification of tumors displaying enhanced sensitivity to this novel anticancer drug.

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“…Besides inhibition of transcription, the specific and stable structures formed by TFO with genomic sites might induce cell cycle arrest. 26 In this study, we utilized this antigene strategy to target survivin in human lung carcinoma A549 cells and our results suggest that the triplex technique is a promising tool for anticancer therapeutics.…”

mentioning

confidence: 85%

Triplex-forming oligodeoxynucleotides targeting survivin inhibit proliferation and induce apoptosis of human lung carcinoma cells

et al. 2003

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Survivin is expressed in most cancers but is undetectable in differentiated adult cells, and plays an important role both in the suppression of apoptosis and mitotic spindle checkpoint; thus it has attracted great interest as a potential drug target. In this study, we investigated the antigene and antiproliferative effects of triplex-forming oligodeoxynucleotides (TFO) targeting survivin in human lung carcinoma A549 cells. Survivin-specific TFOs form stable triplexes under physiological conditions as tested by electrophoretic mobility shift assays. Treatment of A549 cells with survivin-specific but not control TFOs at a concentration of 400 nM in the presence of uptake-enhancing liposome significantly reduced survivin protein level, inhibited cell proliferation, and induced cell apoptosis as demonstrated by immunoblot, cell number counting, and Annexin V-staining. Moreover, we found that the triplex-forming potential of TFOs measured in vitro does not necessarily correlate with the ability of TFOs to affect expression of a targeted gene in vivo. Our results indicate that targeting survivin is a promising alternative strategy for the development of novel anticancer therapeutics.

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Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair

Cited by 323 publications

References 33 publications

A Review of Trabectedin (ET-743): A Unique Mechanism of Action

A Review of Trabectedin (ET-743): A Unique Mechanism of Action

Relevance of the Fanconi anemia pathway in the response of human cells to trabectedin

Triplex-forming oligodeoxynucleotides targeting survivin inhibit proliferation and induce apoptosis of human lung carcinoma cells

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