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Potential of Targeting PDE1C/2A for Suppressing Metastatic Ovarian Cancers
Technical Report,15 Jun 2013,14 Jun 2015
Georgia Regents University Augusta United States
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ERK signaling pathway has long been suggested as a therapeutic target for ovarian cancer progression and metastasis. In our previous studies, we showed that 1 high Erk activity is sensitive to the elevation of intracellular cAMP concentration and 2 agents elevating cellular cAMP suppresses growth of aggressive ovarian cancer cells. This proposal is sought to 1 understand molecular mechanisms associated with forskolinPDE2 inhibitor-induced apoptosis of aggressive ovarian cancer cells and 2 to evaluate the translation value of treating aggressive ovarian cancer cells with forskolin and PDE2 inhibitor in an intraperitoneal xenograft model. In first year of the funding, we showed that knockdown of PDE2A rendered ovarian cancer cells susceptible for forskolin-induced cell growth inhibitionapoptosis. We further showed that combined use of forskolin and Bay60-7550 PDE2 inhibitor downregulates the levels ofBcl2, survivin and phosphorylated Akt whereas induces the expression of Bim1. The effect of forskolinBay60-7550 is clearly mediated by PKA because PKA inhibitor H89 abolished growth inhibition caused by forskolinBay60-7550. In second year of the funding, we evaluated the potential of using cocktail of forskolin and Bay60-7550 to suppress ovarian tumor development. We found that such cocktail is safe to the recipient mice and can effective slowed intraperitoneal metastatic colonization of ovary tumors. We believe that results from our study have built a solid basis for further testing such cocktail in clinic.
APPROVED FOR PUBLIC RELEASE