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Modulation of gene transcription by natural products--a viable anticancer strategy

D'Incalci, Maurizio; Brunelli, Dario; Marangon, E; de Simone, M; Tavecchio, M LU ; Gescher, A and Mantovani, Roberto (2007) In Current Pharmaceutical Design 13(27). p.50-2744
Abstract

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 likely to be 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 DNA-interactive anticancer drugs, e.g. cisplatin, is related to an effect on the transcription of... (More)

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 likely to be 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 DNA-interactive 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.

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author
publishing date
type
Contribution to journal
publication status
published
keywords
Animals, Antineoplastic Agents, Biological Products, Drug Delivery Systems, Humans, Neoplasms, Transcription Factors, Transcription, Genetic, Journal Article, Research Support, Non-U.S. Gov't, Review
in
Current Pharmaceutical Design
volume
13
issue
27
pages
7 pages
publisher
Bentham Science Publishers
external identifiers
  • scopus:35748950735
ISSN
1381-6128
DOI
10.2174/138161207781757097
language
English
LU publication?
no
id
f76bbc64-3d69-44d9-927a-c2dbb666ede2
date added to LUP
2017-03-07 09:15:24
date last changed
2017-06-26 13:25:07
@article{f76bbc64-3d69-44d9-927a-c2dbb666ede2,
  abstract     = {<p>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 likely to be 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 DNA-interactive 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.</p>},
  author       = {D'Incalci, Maurizio and Brunelli, Dario and Marangon, E and de Simone, M and Tavecchio, M and Gescher, A and Mantovani, Roberto},
  issn         = {1381-6128},
  keyword      = {Animals,Antineoplastic Agents,Biological Products,Drug Delivery Systems,Humans,Neoplasms,Transcription Factors,Transcription, Genetic,Journal Article,Research Support, Non-U.S. Gov't,Review},
  language     = {eng},
  number       = {27},
  pages        = {50--2744},
  publisher    = {Bentham Science Publishers},
  series       = {Current Pharmaceutical Design},
  title        = {Modulation of gene transcription by natural products--a viable anticancer strategy},
  url          = {http://dx.doi.org/10.2174/138161207781757097},
  volume       = {13},
  year         = {2007},
}