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 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.
Highlights
There are many ways to define the crucial differences between cancer cells and their normal counterparts, from which they are derived
In the present paper we summarize the evidence for the contention that certain naturally occurring agents can modulate transcriptional regulation, and we proffer the argument that such modulation might be a mechanism which may be profitably exploited in new anticancer drug development
Most striking results have been obtained in CML with the use of Glivec, a tyrosine kinase inhibitor that blocks Bcr/Abl, the fusion gene product that is the pathogenetic lesion typical of the disease
Summary
There are many ways to define the crucial differences between cancer cells and their normal counterparts, from which they are derived. A large body of data supports the notion that the differentiationinducing and antileukemic effects of these compounds is related to a change of the methylation status of the promoters of several genes, that results in cell death/differentiation depending on the cellular model This mechanism is the basis for the clinical use of these compounds in the therapy of some haematological malignancies [10, 11]. Inhibition of DNA methylation and histone deacetylation probably modifies the expression of a large number of genes, possibly including some mechanistically related to carcinogenesis or tumor progression, and some related to normal cell function. Such compounds are potentially interesting as they engage a mode of action different from that of conventional anticancer drugs. The semi-synthetic approach to obtain potent inhibitors that are sufficiently stable to reach the tumor target in vivo in sufficient amounts to exert biological effects is an attractive area of research in the development of novel compounds acting on NF-kB
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