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

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 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

Sp1 transcription factor: A long-standing target in cancer chemotherapy

“…Many of the drugs and natural molecules reviewed here can be considered safe enough (D'Incalci, et al, 2007;Minotti, et al, 2004;Núñez, et al, 2012;Sankpal, et al, 2013), which would support or accelerate their clinical usage. However, experimental data should be handled with care in translational medicine based on inhibiting Sp transcription factors, given that Sp1 and/or Sp3 can cooperatively activate several genes through the interaction with other transcription factors or their DNA-binding sites Vizcaíno, et al, 2012;Wierstra, 2008).…”

Natural Compounds' Activity against Cancer Stem-Like or Fast-Cycling Melanoma Cells

“…Natural compounds are widely used in anticancer therapy and can exert considerable biological activity [19]–[21]. Although their mechanisms of action are often not well defined, most of therapeutic agents derived from natural products are mainly effective at eliminating cancer cells with a high proliferation rate.…”

Protective Effects of Mastic Oil FromPistacia LentiscusVariationChiaAgainst Experimental Growth of Lewis Lung Carcinoma

“…Phytochemicals might influence cancer risk through several activities associated at least in part with disruption of aberrant cellular processes leading to malignancies such as uncontrolled cell proliferation and survival, angiogenesis, and inflammation (7)(8)(9). Although the molecular basis of these actions remains uncertain, many phytochemicals have been shown to directly target several transcription factors possibly because they may have evolutionarily evolved in plants to exert highly specialized functions through modulation of specific gene transcription (10). Monoterpenes comprise a particularly interesting class of phytochemicals with a prominent chemopreventive and chemotherapeutic potential against several cancer types (breast, colon, lung, pancreatic duct adenocarcinoma, etc.)…”