The use of natural products with therapeutic properties is as ancient as human civilization and for a long time mineral, plant and animal products were the main sources of drugs. Worldwide sales of medicinal plants, crude extracts and finished products amounted to US$15 billion in 1999 and it increased to $23 billion in 2002. More interestingly, the influence of natural products upon anticancer drug discovery and design cannot be underestimated. Approximately 60% of all drugs in clinical trials are either a natural product, compounds derived from natural products or contain pharmacophores derived from active natural products. Thus, even today, in the presence of massive numbers of agents from combinatorial libraries, compounds from natural sources are still in the forefront of cancer chemotherapeutics as sources of active drug types, as well as being involved in drug discovery in diseases such as microbial and parasitic infections and the control of cholesterol/lipids, among other functions.
Cancer is a pathologic condition that involves genetic and epigenetic events culminating in neoplastic transformation. Alteration in epigenetic events that regulate the transcriptional activity of genes associated with various signaling pathways can influence multiple stages of tumorigenesis. In cancer cells, an imbalance often exists between histone acetyl transferase and histone deacetylase (HDAC) activities, and current research focuses actively on seeking competitive HDAC inhibitors (HDACi) for chemotherapeutic intervention. HDACi are proving useful for cancer prevention and therapy by virtue of their ability to reactivate the expression of epigenetically silenced genes, including those involved in differentiation, cell cycle regulation, apoptosis, angiogenesis, invasion, and metastasis. Furthermore, epidemiological studies suggest that different diets such as intake of cruciferous vegetables may lower the risk of different cancers, and there is growing interest in identifying the specific chemoprotective constituents and mechanistic insights of their action. Interestingly, it has been observed that cancer cells are more sensitive than nontransformed cells to apoptotic induction by some HDACi. Although the mechanistic basis for this sensitivity is unclear, yet HDACi have emerged as important epigenetic target for single and combinatorial chemotherapy. HDACi derived from diverse sources such as microbial, dietary, and synthetic increase acetylation level of cells and bring about anti-proliferative and apoptotic effects specific to cancer cells by way of their role in cell cycle regulation and expression of epigenetically silenced genes.
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