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Detection of Intracellular Granularity Induction in Prostate Cancer Cell Lines by Small Molecules Using the HyperCyt® High-Throughput Flow Cytometry SystemUniversity of New Mexico Center for Molecular Discovery, Albuquerque, New Mexico, University of New Mexico Cancer Center, Albuquerque, New Mexico, MHaynes{at}salud.unm.edu
University of New Mexico Center for Molecular Discovery, Albuquerque, New Mexico, University of New Mexico Cancer Center, Albuquerque, New Mexico
University of New Mexico Center for Molecular Discovery, Albuquerque, New Mexico, University of New Mexico Cancer Center, Albuquerque, New Mexico
University of New Mexico Center for Molecular Discovery, Albuquerque, New Mexico, Division of Biocomputing, Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
University of New Mexico Center for Molecular Discovery, Albuquerque, New Mexico, Division of Biocomputing, Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
University of New Mexico Center for Molecular Discovery, Albuquerque, New Mexico, Division of Biocomputing, Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
University of New Mexico Center for Molecular Discovery, Albuquerque, New Mexico, Division of Biocomputing, Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
University of New Mexico Center for Molecular Discovery, Albuquerque, New Mexico, University of New Mexico Cancer Center, Albuquerque, New Mexico, Department of Cellular Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
University of New Mexico Center for Molecular Discovery, Albuquerque, New Mexico, University of New Mexico Cancer Center, Albuquerque, New Mexico, Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
University of New Mexico Center for Molecular Discovery, Albuquerque, New Mexico, University of New Mexico Cancer Center, Albuquerque, New Mexico, Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, New Mexico Prostate cancer is a leading cause of death among men due to the limited number of treatment strategies available for advanced disease. Discovery of effective chemotherapeutics involves the identification of agents that inhibit cancer cell growth. Increases in intracellular granularity have been observed during physiological processes that include senescence, apoptosis, and autophagy, making this phenotypic change a useful marker for identifying small molecules that induce cellular growth arrest or death. In this regard, epithelial-derived cancer cell lines appear uniquely susceptible to increased intracellular granularity following exposure to chemotherapeutics. We have established a novel flow cytometry approach that detects increases in side light scatter in response to morphological changes associated with intracellular granularity in the androgen-sensitive LNCaP and androgen-independent PC3 human prostate cancer cell lines. A cell-based assay was developed to screen for small molecule inducers of intracellular granularity using the HyperCyt® high-throughput flow cytometry platform. Validation was performed using the Prestwick Chemical Library, where known modulators of LNCaP intracellular granularity, such as testosterone, were identified. Nonandrogenic inducers of granularity were also detected. A further screen of ~25,000 small molecules led to the identification of a class of aryl-oxazoles that increased intracellular granularity in both cell lines, often leading to cell death. The most potent agents exhibited submicromolar efficacy in LNCaP and PC3 cells. (Journal of Biomolecular Screening. 2009:596-609)
Key Words: HyperCyt® high-throughput flow cytometry • small molecule screening • intracellular granularity • prostate cancer
This version was published on July
1, 2009 Journal of Biomolecular Screening, Vol. 14, No. 6,
596-609 (2009) |
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