The mammalian cell cycle is a tightly controlled process that regulates cell growth and division. Several checkpoints exist, including the G1/S phase checkpoint and the G2/M, or mitotic, checkpoint. Upon activation of either checkpoint, a cells fate is determined and can either continue through the cell cycle, halt and repair itself before going further, or undergo apoptosis. Although it is unclear how a cell determines whether to arrest in the cell cycle or to go through apoptosis, both mechanisms can involve the activation of tumor suppressor protein p53. Regulation of the cell cycle is often lacking somewhat in cancer cells, therefore many inhibitors of the cell cycle are currently in development and clinical trials for the treatment of many cancer types. We have developed a novel analog of cyclin-dependent kinase inhibitor Purvalanol B, termed VMY-1-103 (VMY), which has unique pro-apoptotic properties in cells and has potential as a cancer therapeutic agent.
In all cell lines tested, VMY induces a G2/M cell cycle arrest, consistent with its ability to inhibit cdk1/cyclin B activity. In medulloblastoma cells, VMY treatment has unique properties in mitosis that other cdk inhibitors do not. Treatment of these cells following nocadozole block and release significantly increases time in mitosis, as cells are arrested in metaphase for a prolonged period of time. Furthermore, VMY treatment quickly induces mitotic abnormalities, such as mislocalized chromosomes and merotely in these cells, while the parent compound Purvalanol B and pan-cdk inhibitor Flavopiridol do not. In addition to its effect on the cell cycle, VMY also causes rapid p53-dependent apoptosis in cell lines containing wild-type p53. In LNCaP prostate cancer cells, which are p53 wild-type, siRNA knockdown of p53 diminishes VMY-induced cell cycle arrest and apoptosis. Furthermore, transfection of wild-type p53 into null PC3 cells renders them sensitive to VMY, as does restoration of wild-type p53 in mutant DU145 cells by PRIMA-1. Importantly, VMY induces increased apoptosis in primary prostate cancer cell lines as compared with matched normal prostate cells from the same human patients. Therefore, VMY has great potential as a possibly therapeutic agent to treat many types of cancer.
|Commitee:||Banerjee, Partha, Glazer, Robert, Mueller, Susette, Uren, Aykut|
|School Location:||United States -- District of Columbia|
|Source:||DAI-B 74/04(E), Dissertation Abstracts International|
|Keywords:||Apoptosis, Cell cycle, Prostate cancer, p53|
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