Metformin's Influence on Pancreatic Ductal Adenocarcinoma Metabolism and Chemotherapy Response
Master thesis
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https://hdl.handle.net/11250/3080905Utgivelsesdato
2023Metadata
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Sammendrag
Pancreatic cancer is a highly lethal disease with a 5-year survival rate of approximately 10%. One of the primary reasons for its lethality is the prevalence of chemoresistance. Several studies have found Oxidative Phosphorylation to be a major contributor of Pancreatic Ductal Adenocarcinoma (PDAC) chemoresistance. It has therefore been postulated that inhibiting mitochondrial respiration can mitigate chemoresistance. It is of the upmost importance to investigate this claim to prolong survival outcomes among suffering patients. The commonly prescribed biguanide anti-diabetic drug, metformin, has been found to hinder Oxidative Phosphorylation by inhibiting complex I of the Electron Transport Chain. Metformin may therefore prevent or reverse PDAC chemoresistance when used as an adjuvant treatment with common chemotherapies. Not much research has analyzed the impact of a metformin- chemotherapy adjuvant treatment with clinically relevant conditions. Furthermore, a thorough examination of the molecular impact on PDAC metabolisms in relation to metformin must be conducted. The overall aim of this study is to assess how metformin affects the metabolic profiles of treated PDAC cell lines, and to analyze how a combination of metformin and various chemotherapies impact the growth and viability of PDAC cells grown in 3D. The overarching results show that the effectiveness of metformin strongly depends on the cell line. For example, metformin successfully altered the metabolism and proliferation rates of AsPC-1 cells, but not Panc-1 cells. Furthermore, not all chemotherapies were made to be more effective by a metformin pretreatment. Several chemotherapies did not hinder the growth of PDAC spheroids even when preincubated with metformin. Therefore, the effectiveness of metformin depends on the cell line and the chemotherapy used.