Canagliflozin (CANA) is a sodium-glucose co-transporter 2 (SGLT2) inhibitor used for the treatment of type II diabetes. There is recent evidence suggesting that Canagliflozin has antiproliferative effects against malignant tumours. Canagliflozin is able to inhibit cell growth and cancer progression by inhibiting mitochondrial complex I leading to a reduction in cellular ATP levels. This alteration in the energy status of the cell leads to AMP-activated kinase (AMPK) activation, which in turn downregulates protein synthesis, lipogenesis and induces cell cycle arrest. The aim of this thesis is to explore whether Canagliflozin can be combined with radiation to enhance the outcome of radiation therapy in the treatment of prostate cancer and to further our knowledge on the cellular pathways impacted by Canagliflozin. Proliferation and clonogenic survival assays were used to establish the antiproliferative effect of Canagliflozin in vitro alone and when combined with radiation. Prostate cancer cell lines with different mutation profiles were used to assess the effectiveness of the drug under different radiation doses. A xenograft model was then used to test Canagliflozin’s effects in vivo. PC-3 cells were injected in the flank of balb/c nude mice. Mice were treated with Canagliflozin, radiation or a combined treatment and tumour growth was monitored. Furthermore, a western blot analysis of cells treated with Canagliflozin and radiation was performed to deepen our understanding of the cellular pathways affected by Canagliflozin. Our results show that Canagliflozin has an additive effect when combined with radiation. Canagliflozin was able to effectively downregulate the mTOR pathway, blocking mitosis and leading to cell cycle arrest. These findings provide evidence that Canagliflozin could be used as an adjunct to radiation therapy in clinical settings. / Thesis / Master of Science in Medical Sciences (MSMS) / Radiation therapy is a key therapy for prostate cancer. Although it is very effective at treating early stages of prostate cancer, prostate cancer cells develop resistance to radiation therapy rendering it less effective. One way to overcome this obstacle is by delivering higher doses of radiotherapy. However, this leads to increased side effects caused by radiation on normal tissues surrounding the prostate. An additional potential solution to this problem is administering a drug that can make cancer cells more sensitive to radiotherapy. This way we can deliver lower doses of radiation to avoid side effects while treating the disease. This study focuses on using a drug called Canagliflozin in combination with radiation in order to improve the outcomes of radiotherapy in prostate cancer.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/25849 |
| Date | January 2020 |
| Creators | Mekhaeil, Bassem |
| Contributors | Tsakiridis, Theodoros, Health Sciences |
| Source Sets | McMaster University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis |
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