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

Sheikh, Kathryn; Banerjee, Partha P.; Jagadeesh, Shankar; Grindrod, Scott; Zhang, Li; Paige, Mikell; Brown, Milton L.

doi:10.1021/jm9011615

Cited by 33 publications

(22 citation statements)

References 20 publications

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“…[56] 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.…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

The cellular functions of RASSF1A and its inactivation in prostate cancer

Amin¹,

Banerjee²

2012

J Carcinog

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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.

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Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

The cellular functions of RASSF1A and its inactivation in prostate cancer

Amin¹,

Banerjee²

2012

J Carcinog

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“…Evaluation of effects of YK-4-272 on mouse xenograft was performed as previously reported (20). Briefly, male athymic Balb/c nude mice weighing 18–22 g were injected with 0.3 mL of 3×10 6 PC-3 cells in the subcutaneous tissue of the right axillary region of the body.…”

Section: Methodsmentioning

confidence: 99%

Preclinical Studies of YK-4-272, an Inhibitor of Class II Histone Deacetylases by Disruption of Nucleocytoplasmic Shuttling

et al. 2012

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Purpose The HDAC shuttling inhibitor, YK-4-272 functions by restricting nuclear shuttling of Class II HDACs. Pre-clinical investigations of YK-4-272 bioavailability, pharmacokinetics, in vivo toxicity and tumor growth inhibition were performed to determine its potential as an HDAC shuttling disruptor for use in clinical applications. Methods The solubility, lipophilicity, in vitro metabolic stability, in vitro intestinal permeability, and in vivo pharmacokinetics of YK-4-272 were determined by HPLC methods. The anti-tumor activity of YK-4-272 was determined by monitoring athymic Balb/c nude mice bearing PC-3 xenografts. Results Oral bioavailability of YK-4-272 is supported by its solubility (0.537 mg/mL) and apparent partition coefficient of 2.0. The compound was chemically and metabolically stable and not a substrate for CYP450. In Caco-2 cell transport studies, YK-4-272 was highly permeable. The time-concentration profile of YK- 4-272 in plasma resulted in a Cmax of 2.47 µg/mL at 0.25 h with a AUC of 3.304 µg×h/mL. Treatment of PC-3 tumor xenografts with YK-4-272 showed significant growth delay. Conclusions YK-4-272 is stable and bio-available following oral administration. Growth inhibition of cancer cells and tumors was observed. These studies support advancing YK-4-272 for further evaluation as a novel HDAC shuttling inhibitor for use in cancer treatment.

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“…However, more recent studies showed that curcumin did not cause DNA demethylation in three arbitrarily chosen human cancer cell lines . Mahanine, a plantderived carbazole alkaloid, and a fluorescent carbazole analogue, has been reported to induce the Ras-association domain family 1 (RASSF1) gene in human prostate cancer cells, presumably by inhibiting DNMT activity (Jagadeesh et al, 2007;Sheikh et al, 2010). Nanaomycin A, a quinone antibiotic isolated from a culture of Streptomyces, has been described as the first non S-adenosyl-L-homocysteine (AdoHcy/SAH) analogue acting as a DNMT3B-selective inhibitor that induces genomic demethylation.…”

Section: Wwwintechopencommentioning

confidence: 99%

“…2 inhibited human prostate cancer cell proliferation at 1.5 µM 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).…”

Section: Optimization Of Rg108 Procaine and Mahaninementioning

confidence: 99%