Ecteinascidin 743, a transcription-targeted chemotherapeutic that inhibits MDR1 activation

Jin, Shengkan; Gorfajn, Barbara; Faircloth, Glynn; Scotto, Kathleen W.

doi:10.1073/pnas.97.12.6775

Cited by 190 publications

(126 citation statements)

References 21 publications

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“…At the cell level, trabectedin does not seem to affect constitutive transcription, but only the transcription of activated genes (17). At nanomolar concentrations, trabectedin effectively blocked the activated transcription of genes such as HSP-70 (18) or MDR1 (19). Further studies indicated that, although trabectedin is a DNA minor groove binder, it also has effects on promoters regulated by transcription factors that bind to the major groove (e.g., Sp1; ref.…”

Section: Transcription Regulationmentioning

confidence: 99%

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

D’Incalci

Galmarini

2010

Molecular Cancer Therapeutics

378

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: Transcription Regulationmentioning

confidence: 99%

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

D’Incalci

Galmarini

2010

Molecular Cancer Therapeutics

378

291

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“…NFY is a pivotal factor involved in MDR1 transcription. ET-743 has recently been reported to block the e ects of NFY on MDR1 expression (Jin et al, 2000). Levels of mismatch repair de®ciencies, seen in some cancer cells lines, are also unable to modify the e ect of ET-743 whereas cells de®cient in DNA dependent protein kinase (DNA-PK) appear to be more sensitive to the drug (D'Incalci, 1999).…”

Section: A Minor-grove Dna Inhibitor Et-743mentioning

confidence: 99%

New agents in cancer clinical trials

Adams

Elliott

2000

Oncogene

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“…Besides its superior antitumour activity, ET-743 also efficaciously inhibits the expression of CYP3A4 and MDR1 genes in tissue cultures [24,66]. The inhibition of CYP3A4 and MDR1 gene expression by ET-743 is likely to be mediated through its antagonism of PXR.…”

Section: Antagonism Of Pregnane X Receptor By Ecteinascidin-743mentioning

confidence: 98%

Pregnane X receptor and natural products: beyond drug–drug interactions

Staudinger

Ding

Lichti

2006

Expert Opinion on Drug Metabolism & Toxicology

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The pregnane X receptor (PXR, NR1I2) is a member of the nuclear receptor superfamily that is activated by a myriad of compounds and natural products in clinical use. Activation of PXR represents the basis for several clinically important drug-drug interactions. Although PXR activation has undesirable effects in patients on combination therapy, it also mediates the hepatoprotective effects exhibited by some herbal remedies. This review focuses on PXR activation by natural products and the potential therapeutic opportunities presented. In particular, the biological effects of St. John's Wort, gugulipid, kava kava, Coleus forskolii, Hypoxis, Sutherlandia, qing hao, wu wei zi, gan cao and other natural products are discussed. The impact of these natural products on drug metabolism and hepatoprotection is highlighted in the context of activation and antagonism of PXR.

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Ecteinascidin 743, a transcription-targeted chemotherapeutic that inhibits MDR1 activation

Cited by 190 publications

References 21 publications

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

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

New agents in cancer clinical trials

Pregnane X receptor and natural products: beyond drug–drug interactions

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