Fluorescent Epigenetic Small Molecule Induces Expression of the Tumor Suppressor Ras-Association Domain Family 1A and Inhibits Human Prostate Xenograft

Department of Oncology, Georgetown University, 3970 Reservoir Road NW, Washington, DC 20057, USA.
Journal of Medicinal Chemistry (Impact Factor: 5.45). 02/2010; 53(6):2376-82. DOI: 10.1021/jm9011615
Source: PubMed


Epigenetic silencing of Ras-association domain family 1A (RASSF1A) protein in cancer cells results in a disruption of cell cycle control, genetic instability, enhanced cell motility, and apoptotic resistance. Ectopic expression of RASSF1A reverses this tumorigenic phenotype. Thus, small molecules with the ability to restore RASSF1A expression may represent a new class of therapeutic agents. Recently, we designed and synthesized a fluorescent carbazole analogue of mahanine (alkaloid from Murraya koenigii) that restored RASSF1A mRNA expression. Our fluorescent lead compound up-regulated RASSF1A in vitro, potently inhibited human prostate cancer cell proliferation, and fluoresced at a visible wavelength, allowing for the observation of intracellular distribution. The small molecule lead was not acutely toxic up to 550 mg/kg, and dosing at 10 mg/kg reduced human xenograft tumor volume by about 40%.

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    • "Similar effects were observed in prostate cancer cells treated with a synthetic fluorescent analogue (Ked-4-69) of mahanine.[57] Mahanine and Ked-4-69 appear to judiciously inhibit DNMT translocation.[57] However, further studies are necessary to confirm whether mahanine or its analogs restore RASSF1A without disrupting epigenetic modifications across the genome. "
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    ABSTRACT: Epigenetic events significantly impact the transcriptome of cells and often contribute to the onset and progression of human cancers. RASSF1A (Ras-association domain family 1 isoform A), a well-known tumor suppressor gene, is frequently silenced by epigenetic mechanisms such as promoter hypermethylation in a wide range of cancers. In the past decade a vast body of literature has emerged describing the silencing of RASSF1A expression in various cancers and demonstrating its ability to reverse the cancerous phenotype when re-expressed in cancer cells. However, the mechanisms by which RASSF1A exerts its tumor suppressive properties have not been entirely defined. RASSF1A appears to mediate three important cellular processes: microtubule stability, cell cycle progression, and the induction of apoptosis through specific molecular interactions with key factors involved in these processes. Loss of function of RASSF1A leads to accelerated cell cycle progression and resistance to apoptotic signals, resulting in increased cell proliferation. In this review, we attempt to summarize the current understanding of the biological functions of RASSF1A and provide insight that the development of targeted drugs to restore RASSF1A function holds promise for the treatment of prostate cancer.
    Journal of Carcinogenesis 02/2012; 11(1):3. DOI:10.4103/1477-3163.93000
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    • "Compound '9' in Fig. 2 inhibited human prostate cancer cell proliferation at 1.5 ┬ÁM and also showed DNMT inhibition activity without the cytotoxic effects seen with mahanine treatment. Inhibition of DNMT was proposed as the event leading to the restoration of RASSF1A expression (Sheikh et al., 2010). "

    Drug Development - A Case Study Based Insight into Modern Strategies, 12/2011; , ISBN: 978-953-307-257-9
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    • "Other areas under fierce development in the field of target-specific therapeutics include exploration of innovative strategies to reactivate tumor suppressors and inhibit oncogenic transcription factor complexes. An example of the former is the discovery and characterization of small molecules that reverse the epigenetic silencing of RASSF1A tumor suppressor protein in preclinical models (Sheikh et al., 2010). Unlike enzymes, transcriptional factors are generally entailed " undruggable " . "

    Frontiers in Oncology 05/2011; 1:4. DOI:10.3389/fonc.2011.00004
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