Selective Effects of the Anticancer Drug Yondelis (ET-743) on Cell-Cycle Promoters

Minuzzo, Mario; Ceribelli, Michele; Pitarque-Martì, Marià; Borrelli, S.; Erba, Eugenio; DiSilvio, Alberto; D’Incalci, Maurizio; Mantovani, Roberto

doi:10.1124/mol.105.013615

Cited by 38 publications

(24 citation statements)

References 37 publications

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“…Other promoters were not significantly affected. These data corroborate the idea that ET-743 is not a general inhibitor of transcription, but that it acts preferentially on some promoters by inhibiting or inducing their activity [31]. The conclusion is also supported by gene Although we have no formal demonstration that the antitumor activity of ET 743 is related to its effects on transcriptional regulation, we can exclude that it acts by inhibiting DNA synthesis.…”

Section: Marine Compounds As Modulators Of Gene Transcriptionsupporting

confidence: 76%

“…However some genes that were affected, like c-fos, did not contain CCAAT-boxes, indicating that the effects of ET-743 were not specific for NF-Y but that other transcription factors were inhibited. Further studies were performed to investigate the effect of ET-743 on the promoters of genes (cyclin E, E2F1, TK, DHFR, cyclin A, cdc2 and cyclin B2) that regulate the cell cycle by using NIH-3T3 fibroblasts stably transfected with reporter vectors, containing either the CAT or luciferase genes, together with the thyromycin resistance containing vector [31]. Cells synchronized in G0 were stimulated to grow by serum addition, and at several time points the transcriptional activity of these promoters were studied in untreated and ET-743 treated cells.…”

Section: Marine Compounds As Modulators Of Gene Transcriptionmentioning

confidence: 99%

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Modulation of Gene Transcription by Natural Products - A Viable Anticancer Strategy

D’Incalci

Brunelli²,

Marangon³

et al. 2007

CPD

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Drug design based on the structure of specific enzymes playing a role in carcinogenesis, e.g. tyrosine kinases, has been successful at identifying novel effective anticancer drugs. In contrast, no success has been achieved in drug design attempts, in which transcription factors or DNA-transcription factor complexes involved in the pathogenesis of human neoplasms were targeted. This failure is probably due to the fact that the mechanism of transcription regulation is probably too complex and still too inadequately understood to be a suitable target for drug design.It seems plausible that the high selectivity of some human tumors to some DNAinteractive anticancer drugs, e.g. cisplatin, is related to an effect on the transcription of genes that are crucial for those tumors. In this article we propose that some natural products have evolutionarily evolved to exert highly specialized functions, including modulation of the transcriptional regulation of specific genes. We discuss in detail the marine natural product Yondelis (Trabectedin, ET-743) that is effective against some soft tissue sarcoma, possibly because it interferes with the aberrant transcription mechanism in these tumors. In addition we highlight the existing evidence that many different natural products are effective inhibitors of NF-kB, a transcription factor that plays a crucial role in inflammation and cancer, indicating that some of these compounds might possess antitumor properties. We propose that large-scale characterization of natural products acting as potential modulators of gene transcription is a realistic and attractive approach to discover compounds therapeutically effective against neoplastic diseases characterized by specific aberrations of transcriptional regulation.3

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Section: Marine Compounds As Modulators Of Gene Transcriptionsupporting

confidence: 76%

Section: Marine Compounds As Modulators Of Gene Transcriptionmentioning

confidence: 99%

Modulation of Gene Transcription by Natural Products - A Viable Anticancer Strategy

D’Incalci

Brunelli²,

Marangon³

et al. 2007

CPD

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“…Afterward, MPF is reactivated rapidly to enter meiosis II and is maintained at high level during the MII arrest [15]. In culture cells, the chromatin around the genomic region of Cdc2a is acetylated in the histone H4 [16]. Conversely, histone acetylation of H4K12 is altered in oocytes when the kinase activity and synthesis of the CDC2A protein are inhibited [11].…”

Section: Introductionmentioning

confidence: 94%

Aging Alters Histone H4 Acetylation and CDC2A in Mouse Germinal Vesicle Stage Oocytes1

Manosalva

González

2009

Biology of Reproduction

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The reproductive potential of mammals decreases with aging, until reaching infertility. One reason for aging-related infertility is the decrease of the reproductive capability of old oocytes. It was found previously that gene expression, histone acetylation, and protein function are altered by aging in metaphase II (MII) stage oocytes. MII oocytes develop from germinal vesicle (GV)-stage oocytes. Here, we hypothesized that the defects of old MII oocytes arise at the GV stage. To prove this hypothesis, we examined the acetylations of histone H4 at lysines 5 (H4K5), 8 (H4K8), 12 (H4K12), and 16 (H4K16) in old GV and MII oocytes. We found that acetylation of H4K12 and H4K16 decreased in old GV oocytes. Acetylation of H4K12 later increased in old MII oocytes. We also examined expression of Cdc2a, a gene related to H4K12 acetylation. Cdc2a expression increased in old nonsurrounded nucleolus (NSN) oocytes but decreased in old MII oocytes. On the other hand, the protein and kinase activities of CDC2A decreased in both GV and MII old oocytes. Finally, we showed that correction of the histone deacetylation of old oocytes at the GV stage restores younglike levels of H4K12 acetylation and CDC2A protein at the MII stage. These data support our hypothesis that abnormalities of histone acetylation at the GV stage are the cause of alterations at the MII stage. Our study provides evidence for strategies targeting the GV stage of oocytes to overcome aging-induced infertility.

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“…20), and studies also indicated that the drug is not active on all activated genes (e.g., methallothionein, CYP3A4; ref. 21). In addition, trabectedin can inhibit (e.g., DHFR, TK, or cyclin B2) or stimulate (e.g., cyclin E) the activated transcription process.…”

Section: Transcription Regulationmentioning

confidence: 99%

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

D’Incalci

Galmarini

2010

Molecular Cancer Therapeutics

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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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Selective Effects of the Anticancer Drug Yondelis (ET-743) on Cell-Cycle Promoters

Cited by 38 publications

References 37 publications

Modulation of Gene Transcription by Natural Products - A Viable Anticancer Strategy

Modulation of Gene Transcription by Natural Products - A Viable Anticancer Strategy

Aging Alters Histone H4 Acetylation and CDC2A in Mouse Germinal Vesicle Stage Oocytes1

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

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