PDE5 Inhibitor (Sildenafil) for Ameliorating Androgen Deprivation Therapy (ADT)-Induced Cardiotoxicity
Technical Report,15 Jul 2018,14 Jul 2019
University of Nebraska Medical Center Biochemistry and Molecular Biology Omaha United States
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Androgen deprivation therapy ADT is the primary systemic therapy for treating locally advanced or metastatic prostate cancer PCa. Since 1990, the majority of locally advanced and metastatic PCa patients received GnRH agonists as first-line ADT treatment. Despite its positive effect on PCa patient survival, ADT cause various adverse effects, including increased cardiovascular risk factors and cardiotoxicity. Lifespans extension, early use of ADT, and second-line treatment with next-generation androgen receptor pathway inhibitors would further extend the duration of ADT and possibly increase the risk of ADT-induced cardiotoxicity. However, currently no experimental study has reported the detrimental effect of GnRH agonist in cardiac tissue and no therapeutic strategy has been developed or even conceptualized to prevent GnRH agonist-induced cardiac dysfunction. The underlying mechanism and association between GnRH agonists and cardiovascular events is also not clear. In the proposed research, our objective is to determine the protective role and elucidate the molecular mechanisms of sildenafil against cardiotoxicity caused by GnRH agonists in vitro and in vivo. Here, we update our accomplishment with respect to submitted proposal. We have successfully generated and validate the Pten null PCa GEMMs for the project. In addition, we have also established GEMMs derived syngeneic cell lines. Further, our in vitro studies show that GnRH agonists induce cardiac cell death and sildenafil citrate is able to prevent the agonists induced cardiac cell death. Further, the dose dependent escalation pilot study to determine the optimal dose of GnRH agonists in inducing cardiotoxic events and sildenafil citrate in preventing the GnRH effects is ongoing.
- Medicine and Medical Research