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

A Correction to this article was published on 01 November 2001

Abstract

While investigating the novel anticancer drug ecteinascidin 743 (Et743), a natural marine product isolated from the Caribbean sea squirt, we discovered a new cell-killing mechanism mediated by DNA nucleotide excision repair (NER). A cancer cell line selected for resistance to Et743 had chromosome alterations in a region that included the gene implicated in the hereditary disease xeroderma pigmentosum (XPG, also known as Ercc5). Complementation with wild-type XPG restored the drug sensitivity. Xeroderma pigmentosum cells deficient in the NER genes XPG, XPA, XPD or XPF were resistant to Et743, and sensitivity was restored by complementation with wild-type genes. Moreover, studies of cells deficient in XPC or in the genes implicated in Cockayne syndrome (CSA and CSB) indicated that the drug sensitivity is specifically dependent on the transcription-coupled pathway of NER. We found that Et743 interacts with the transcription-coupled NER machinery to induce lethal DNA strand breaks.

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Figure 1: SKY karyotype and CGH profile of chromosome 13 in HCT116 (upper) and HCT116/ER5 cells (lower).
Figure 2: Deletion of XPG in HCT116/ER5 cells.
Figure 3: Restoration of DNA NER and Et743 sensitivity in XPG-complemented HCT116/ER5 cells.
Figure 4: Cytotoxicity of Et743 transcription-coupled repair.
Figure 5: Accumulation of DNA SSBs in TC-NER–proficient fibroblasts.
Figure 6: Model for TC-NER–mediated cytotoxicity of Et743.

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References

  1. Rinehart, K.L. et al. Bioactive compounds from aquatic and terrestrial sources. J. Nat. Prod. 53, 771–792 (1990).

    Article  CAS  Google Scholar 

  2. Rinehart, K.L. Antitumor compounds from tunicates. Med. Res. Rev. 20, 1–27 (2000).

    Article  CAS  Google Scholar 

  3. Martinez, E.J., Owa, T., Schreiber, S.L. & Corey, E.J. Phthalascidin, a synthetic antitumor agent with potency and mode of action comparable to ecteinascidin 743. Proc. Natl. Acad. Sci. USA 96, 3496–501 (1999).

    Article  CAS  Google Scholar 

  4. Delaloge, S. et al. ecteinascidin-743: A marine-derived compound in advanced, pretreated sarcoma patients—preliminary evidence of activity. J. Clin. Oncol. 19, 1248–1255 (2001).

    Article  CAS  Google Scholar 

  5. Ryan, D.P. et al. Phase I and pharmacokinetic study of ecteinascidin 743 administered as a 72-hour continuous intravenous infusion in patients with sold malignancies. Clin. Cancer. Res. 7, 231–242 (2001).

    CAS  PubMed  Google Scholar 

  6. Sakai, R., Rinehart, K.L., Guan, Y. & Wang, A.H. Additional antitumor ecteinascidins from a Caribbean tunicate: Crystal structures and activities in vivo. Proc. Natl. Acad. Sci. USA 89, 11456–11460 (1992).

    Article  CAS  Google Scholar 

  7. Seaman, F.C. & Hurley, L.H. Molecular basis for the DNA sequence selectivity of ecteinascidin 736 and 743: Evidence for the dominant role of direct readout via hydrogen bonding. J. Am. Chem. Soc. 120, 13028–13041 (1998).

    Article  CAS  Google Scholar 

  8. Pommier, Y. et al. DNA sequence- and structure-selective alkylation of guanine N2 in the DNA minor groove by ecteinascidin 743, a potent antitumor compound from the Caribbean tunicate Ecteinascidia turbinata. Biochemistry 35, 13303–13309 (1996).

    Article  CAS  Google Scholar 

  9. Takebayashi, Y., Pourquier, P., Yoshida, A., Kohlhagen, G. & Pommier, Y. Poisoning of human DNA topoisomerase I by ecteinascidin 743, an anticancer drug that selectively alkylates DNA in the minor groove. Proc. Natl. Acad. Sci. USA 96, 7196–7201 (1999).

    Article  CAS  Google Scholar 

  10. Taamma, A. et al. Phase I and pharmacokinetic study of ecteinascidin-743, a new marine compound, administered as a 24-hour continuous infusion in patients with solid tumors. J. Clin. Oncol. 19, 1256–1265 (2001).

    Article  CAS  Google Scholar 

  11. Damia, G. et al. Unique pattern of ET-743 activity in different cellular systems with defined deficiencies in DNA-repair pathways. Int. J. Cancer 92, 583–588 (2001).

    Article  CAS  Google Scholar 

  12. Takebayashi, Y., Goldwasser, F., Urasaki, Y., Kohlhagen, G. & Pommier, Y. ecteinascidin 743 induces protein-linked DNA breaks in human colon carcinoma HCT116 cells and is cytotoxic independently of topoisomerase I expression. Clin. Cancer Res. 7, 185–191 (2001).

    CAS  PubMed  Google Scholar 

  13. Minuzzo, M. et al. Interference of transcriptional activation by the antineoplastic drug ecteinascidin-743. Proc. Natl. Acad. Sci. USA 97, 6780–6784 (2000).

    Article  CAS  Google Scholar 

  14. Jin, S., Gorfajn, B., Faircloth, G. & Scotto, K.W. ecteinascidin 743, a transcription-targeted chemotherapeutic that inhibits MDR1 activation. Proc. Natl. Acad. Sci. USA 97, 6775–6779 (2000).

    Article  CAS  Google Scholar 

  15. Papadopoulos, N. et al. Mutation of a mutL homolog in hereditary colon cancer. Science 263, 1625–1629 (1994).

    Article  CAS  Google Scholar 

  16. Ghadimi, B.M. et al. Centrosome amplification and instability occurs exclusively in aneuploid, but not in diploid colorectal cancer cell lines, and correlates with numerical chromosomal aberrations. Genes Chromosom. Cancer 27, 183–190 (2000).

    Article  CAS  Google Scholar 

  17. Emmert, S., Kobayashi, N., Khan, S.G. & Kraemer, K.H. The xeroderma pigmentosum group C gene leads to selective repair of cyclobutane pyrimidine dimers rather than 6–4 photoproducts. Proc. Natl. Acad. Sci. USA 97, 2151–2156 (2000).

    Article  CAS  Google Scholar 

  18. Mu, D., Wakasugi, M., Hsu, D.S. & Sancar, A. Characterization of reaction intermediates of human excision repair nuclease. J. Biol. Chem. 272, 28971–28979 (1997).

    Article  CAS  Google Scholar 

  19. Bergmann, E. & Egly, J. Trichothiodystrophy, a transcription syndrome. Trends Genet. 17, 279–286 (2001).

    Article  CAS  Google Scholar 

  20. Batty, D.P. & Wood, R.D. Damage recognition in nucleotide excision repair of DNA. Gene 241, 193–204 (2000).

    Article  CAS  Google Scholar 

  21. Hoeijmakers, J.H.J. From Xeroderma pigmentosum to the biological clock contributions of Dirk Bootsma to human genetics. Mut. Res. 485, 43–59 (2001).

    Article  CAS  Google Scholar 

  22. Wood, R.D. DNA repair in eukaryotes. Annu. Rev. Biochem. 65, 135–167 (1996).

    Article  CAS  Google Scholar 

  23. de Laat, W.L., Jaspers, N.G. & Hoeijmakers, J.H. Molecular mechanism of nucleotide excision repair. Genes Dev. 13, 768–785 (1999).

    Article  CAS  Google Scholar 

  24. Evans, E., Moggs, J.G., Hwang, J.R., Egly, J.M. & Wood, R.D. Mechanism of open complex and dual incision formation by human nucleotide excision repair factors. EMBO J. 16, 6559–6573 (1997).

    Article  CAS  Google Scholar 

  25. Selby, C.P. & Sancar, A. Cockayne syndrome group B protein enhances elongation by RNA polymerase II. Proc. Natl. Acad. Sci. USA 94, 11205–11209 (1997).

    Article  CAS  Google Scholar 

  26. van Gool, A.J. et al. The Cockayne syndrome B protein, involved in transcription-coupled DNA repair, resides in an RNA polymerase II-containing complex. EMBO J. 16, 5955–5965 (1997).

    Article  CAS  Google Scholar 

  27. Lindahl, T. & Wood, R.D. Quality control by DNA repair. Science 286, 1897–1905 (1999).

    Article  CAS  Google Scholar 

  28. Zewail-Foote, M. & Hurley, L.H. ecteinascidin 743: A minor groove alkylator that bends DNA toward the major groove. J. Med. Chem. 42, 2493–2497 (1999).

    Article  CAS  Google Scholar 

  29. Kohn, K.W. DNA filter elution: a window on DNA damage in mammalian cells. Bioessays 18, 505–513 (1996).

    Article  CAS  Google Scholar 

  30. Venter, J.C. et al. The sequence of the human genome. Science 291, 1304–1351 (2001).

    Article  CAS  Google Scholar 

  31. Chen, A.Y. & Liu, L.F. DNA Topoisomerases: Essential enzymes and lethal targets. Annu. Rev. Pharmacol. Toxicol. 94, 194–218 (1994).

    Google Scholar 

  32. Pommier, Y., Pourquier, P., Fan, Y. & Strumberg, D. Mechanism of action of eukaryotic DNA topoisomerase I and drugs targeted to the enzyme. Biochim. Biophys. Acta 1400, 83–105 (1998).

    Article  CAS  Google Scholar 

  33. Lambert, B., Roques, B.P. & Le Pecq, J.B. Induction of an abortive and futile DNA repair process in E. coli by the antitumor DNA bifunctional intercalator, ditercalinium: Role in polA in death induction. Nucleic Acids Res. 16, 1063–1078 (1988).

    Article  CAS  Google Scholar 

  34. Schrock, E. et al. Multicolor spectral karyotyping of human chromosomes. Science 273, 494–497 (1996).

    Article  CAS  Google Scholar 

  35. Zimonjic, D.B., Pollock, J., Westerfield, P., Popescu, N. & Ley, J.T. Acquired, non-random chromosomal abnormalities associated with the development of acute promyelocytic leukemia in transgenic mice. Proc. Natl. Acad. Sci. USA 97, 13306–13311 (2000).

    Article  CAS  Google Scholar 

  36. Khan, S.G. et al. Xeroderma pigmentosum group C splice mutation associated with autism and hypoglycinemia. J. Invest. Dermatol. 111, 791–796 (1998); erratum: 112, 402 (1999).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank K.W. Kohn for helpful discussions and G. Faircloth for supplying Et743. S.E. was supported in part by a grant from the Deutsche Forschungsgemeinschaft.

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Correspondence to Yves Pommier.

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Takebayashi, Y., Pourquier, P., Zimonjic, D. et al. Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair. Nat Med 7, 961–966 (2001). https://doi.org/10.1038/91008

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