Emerging roles for modulation of microRNA signatures in cancer chemoprevention.
ABSTRACT miRNAs are small endogenous non-coding RNAs, approximately 21-nucleotides in length, which are shown to regulate an array of cellular processes such as differentiation, cell cycle, cell proliferation, apoptosis, and angiogenesis which are important in cancer. miRNAs can function as both tumor promoters (oncomiRs) or tumor suppressors by their ability to target numerous biomolecules that are important in carcinogenesis. Aberrant expression of miRNAs is correlated with the development and progression of tumors, and the reversal of their expression has been shown to modulate the cancer phenotype suggesting the potential of miRNAs as targets for anti-cancer drugs. Several chemopreventive phytochemicals like epigallocatechin-3-gallate, curcumin, isoflavones, indole-3-carbinol, resveratrol, and isothiocyanate have been shown to modulate the expression of numerous miRNAs in cancer cells that lead to either abrogation of tumor growth or sensitization of cancer cells to chemotherapeutic agents. This review focuses on the putative role(s) of miRNAs in different aspects of tumorigenesis and at various stages of early drug discovery that makes them a promising class of drug targets for chemopreventive intervention in cancer. We summarize the current progress in the development of strategies for miRNA-based anti-cancer therapies. We also explore the modulation of miRNAs by various cancer chemopreventive agents and the role of miRNAs in drug metabolism. We will discuss the role of miRNAs in cancer stem cells and epithelial-to-mesenchymal transition; and talk about how modulation of miRNA expression relates to altered glycosylation patterns in cancer cells. In addition, we consider the role of altered miRNA expression in carcinogenesis induced by various agents including genotoxic and epigenetic carcinogens. Finally, we will end with a discussion on the potential involvement of miRNAs in the development of cancer chemoresistance. Taken together, a better understanding of the complex role(s) of miRNAs in cancer may help in designing better strategies for biomarker discovery or drug targeting of miRNAs and/or their putative protein targets.
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ABSTRACT: We have developed SMMRNA, an interactive database, available at http://www.smmrna.org, with special focus on small molecule ligands targeting RNA. Currently, SMMRNA consists of ∼770 unique ligands along with structural images of RNA molecules. Each ligand in the SMMRNA contains information such as Kd, Ki, IC50, ΔTm, molecular weight (MW), hydrogen donor and acceptor count, XlogP, number of rotatable bonds, number of aromatic rings and 2D and 3D structures. These parameters can be explored using text search, advanced search, substructure and similarity-based analysis tools that are embedded in SMMRNA. A structure editor is provided for 3D visualization of ligands. Advance analysis can be performed using substructure and OpenBabel-based chemical similarity fingerprints. Upload facility for both RNA and ligands is also provided. The physicochemical properties of the ligands were further examined using OpenBabel descriptors, hierarchical clustering, binning partition and multidimensional scaling. We have also generated a 3D conformation database of ligands to support the structure and ligand-based screening. SMMRNA provides comprehensive resource for further design, development and refinement of small molecule modulators for selective targeting of RNA molecules.Nucleic Acids Research 10/2013; · 8.28 Impact Factor
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ABSTRACT: Hepatocellular cancer is a hypervascular cancer characterized by rapid progression as well as resistance to chemotherapy. Drug resistance arises from the alteration of many molecules, including oncogenes, tumor suppressor genes and miRNAs. This review evaluates the advances of drug resistance-related miRNAs in hepatocellular cancer, and analyzes the value of them as prognostic biomarkers and therapeutic targets. This review also discusses the limitations of miRNA-based therapy, and envisages future developments toward the clinical applications of drug resistance-related miRNAs.Expert review of gastroenterology & hepatology 02/2014;
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ABSTRACT: Curcumin is a well-known dietary polyphenol derived from the rhizomes of turmeric, an Indian spice. The anticancer effect of curcumin has been demonstrated in many cell and animal studies, and recent research has shown that curcumin can target cancer stem cells (CSCs). CSCs are proposed to be responsible for initiating and maintaining cancer, and contribute to recurrence and drug resistance. A number of studies have suggested that curcumin has the potential to target CSCs through regulation of CSC self-renewal pathways (Wnt/β-catenin, Notch, Sonic Hedgehog) and specific microRNAs involved in acquisition of epithelial-mesenchymal transition (EMT). The potential impact of curcumin, alone or in combination with other anticancer agents, on CSCs was evaluated as well. Furthermore, the safety and tolerability of curcumin have been well-established by numerous clinical studies. Importantly, the low bioavailability of curcumin has been dramatically improved through the use of structural analogues or special formulations. More clinical trials are underway to investigate the efficacy of this promising agent in cancer chemoprevention and therapy. In this article, we review the effects of curcumin on CSC self-renewal pathways and specific microRNAs, as well as its safety and efficacy in recent human studies. In conclusion, curcumin could be a very promising adjunct to traditional cancer treatments.Cancer letters 01/2014; · 4.86 Impact Factor