Student Theses, Dissertations and Capstones

Document Type

Dissertation - NSU Access Only

Degree Name

Doctor of Philosophy (PhD) in Pharmacy

First Advisor

Malav Trivedi

Defense Date

1-1-2022

Abstract

Background: Metformin is a biguanide derivative from the Galega officinalis plant and is the most used glucose-lowering drug to manage type 2 diabetes. Besides its antihyperglycemic mechanism, metformin has been shown to be beneficial to a wide spectrum of diseases, especially prostate cancer. Prostate cancer is the second leading cause of cancer-related death in the United States and is currently ranked fifth worldwide. Despite advances in treatment modalities, the lack of effective treatment to properly manage prostate cancer remains a major challenge. This challenge has been linked to the underlying supportive metabolic and molecular pathways that enable cancer cells to evade treatment cytotoxicity, reflecting adaptive mechanisms. During the preceding decade, studies have demonstrated that metformin targets multiple molecular and metabolic pathways, such as androgen signaling, cell cycle, and cellular bioenergetics. Study: I studied the effects of metformin and the involvement of AMPK signaling on mitochondrial oxidative metabolism, thiol metabolites, and cell growth in LNCaP and PC3 prostate cancer cells. Gene expression of redox- and methylation-related genes was measured in metformin-treated cells with or without the AMPK inhibitor SBI0206965. Also, I investigated whether these metabolic effects are mediated by downregulating androgen receptor (AR) signaling in LNCaP prostate cancer cells. Results: Metformin downregulated oxidative phosphorylation with no observable changes of glycolysis in LNCaP and PC3 cells. Redox-related thiols were significantly downregulated in metformin-treated prostate cancer cells, which was associated with a compensatory increase in mRNA expression of redox-related enzymes. Notably, these effects were not counteracted by the presence of SBI0206965. Findings from the comparison of prostate cancer cells showed that metformin promoted a pro-oxidative state in LNCaP and PC3 prostate cancer cells, as reflected by a decrease in OCR levels and their cellular antioxidant capacity, respectively. These metabolic effects of metformin were accompanied by a dose-dependent decrease in cell growth. Bicalutamide (androgen receptor inhibitor) and metformin significantly upregulated SAM and the SAM/SAH ratio in LNCaP cells; however, the GSH and GSH/GSSG were not significantly affected. Notably, these effects were potentiated by the presence of metformin. Conclusion: Metformin promotes cellular oxidative stress in prostate cancer cells by altering their cellular bioenergetic status and antioxidant capacity. A metformin-induced increase in cellular methylation capacity may also contribute towards altered redox status and promote inhibition of cell growth in prostate cancer cells. Such metabolic effects provide the rationale to explore these metabolic pathways as potential therapeutic targets for cancer therapy. The use of metabolic modulators as an adjuvant therapy may improve the effectiveness of conventional treatments, thus reducing the likelihood of chemotherapy resistance and also decreasing the dose of required treatment.

Subject Categories

Pharmacy and Pharmaceutical Sciences

Keywords

Bioenergetics; Glutathione; Metfromin; Oxidative Stress; Prostate Cancer; Transsulfuration Pathway

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