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Frederick R. Krafcik, Jr., Matthew W. Wilson, Michael A. Dyer; Targeting Neuronal Differentiation Pathways in Retinoblastoma. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2480.
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We have recently carried out comprehensive molecular, cellular and genetic analyses of human and mouse retinoblastomas. These data suggest that neuronal differentiation is an important feature of this pediatric cancer. We have now begun testing and identifying novel chemical compounds against retinoblastoma (Rb) for the further purposes of: (a) Achieving a tumoricidal effect and (b) improving our understanding of the role of neuronal differentiation in disease progression.
We screened a large collection of FDA-approved drugs and biologically active compounds against three retinoblastoma cell lines in triplicate dose response. Beyond chemotherapeutics, the most active group of compounds were the phenothiazines. These are anti-psychotics that are used to block catecholamine and biological amine receptors in neurons. To explore the connection between catecholamines and retinoblastoma cell growth we tested an expanded collection of phenothiazines and related compounds. We found that a subset of compounds are highly active against retinoblastoma and this activity correlates with the expression of particlar receptors in human and mouse retinoblastoma. We also tested the mechanism of action of these compounds and extended our studies to in vivo animal models.
There is a striking correlation between target, cheminformatics of phenothiazines, and expression of particular catecholamine/biological amine transporters and downstream effectors in retinoblastoma. These compounds are active in cell culture and in vivo and they act by slowing cell proliferation with little effect on cell death.
Our preliminary data, viewed alongside recent data from other groups (see, e.g, Tzadok, Beery, et al Int J Oncology (2010)), indicate that psychotropic compounds generally, and anti-psychotic compounds specifically, may play significant roles as anti-tumor agents. Our studies also highlight the importance of studying the differentiation of tumor cells and the role of those pathways in tumor progression.
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