Date of Award

2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Pharmaceutical Sciences

Department

Pharmaceutical Sciences

First Advisor

Avinash Kumar

Second Advisor

Anait Levenson

Committee Chair and Members

Avinash Kumar, Co-Chair

Anait Levenson, Co-Chair

Eun Jung Park

Grazia Stagni

Yan Dong

Keywords

Androgen, Dietary chemoprevention, Gnetin C, Oncogenic MTA1, Prostate cancel, Therapeutic strategies

Abstract

Prostate cancer is common among aging men. Despite current management, it continues to be associated with a high mortality rate. A need, therefore, exists for improved treatment approaches that target every stage of the disease. In this study, we investigated the efficacy of Gnetin C, a resveratrol dimer found abundantly in melinjo (Gnetum gnemon) seeds, across three different treatment modalities. The first involved a Gnetin C-supplemented diet as a chemopreventive strategy in a high-risk transgenic mouse model which overexpresses MTA1 on a background of Pten heterozygosity (R26MTA1; Pten+/f). The second involved the administration of Gnetin C by intraperitoneal (i.p.) injection as a therapeutic strategy in a more aggressive transgenic mouse model which overexpresses MTA1 on a background of Pten loss (R26MTA1; Ptenf/f). The third involved i.p. Gnetin C administered as monotherapy and combination therapy (with enzalutamide) in a xenograft-generated model for highly aggressive castrate-resistant prostate cancer. Our chemopreventive studies demonstrated that mice fed Gnetin C diets exhibited significantly less PIN foci, cellular proliferation, angiogenesis, and systemic inflammation. Gnetin C-fed mice also exhibited reduced expression of MTA1 with an upregulation of PTEN. We found that mice injected with Gnetin C as a therapeutic strategy exhibited favorable histopathology with fewer PIN foci, reduced proliferation and angiogenesis, and an increase in apoptosis. Serum from these mice showed a reduction in pro-inflammatory cytokines, and prostate tissue expressed less MTA1 . The CRPC xenograft study demonstrated that Gnetin C treatment was associated with favorable histopathology, reduced expression of MTA1, full-length AR, and truncated AR-V7. Results also showed that combination with enzalutamide could offer benefits over monotherapy. Finally, from our pharmacokinetic studies of Gnetin C, we were able to estimate parameters, such as systemic exposure or AUC (809 mcg.h/L), half-life (1.7 h), and clearance (30.9 L/h/kg). Altogether, this data provides evidence for the use of Gnetin C as a novel anticancer agent that can target different stages of prostate cancer in different modes of administration.

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