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.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22363号 / 医博第4604号 / 新制||医||1043(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 川口 義弥, 教授 富樫 かおり, 教授 上本 伸二 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

In this work a method for determination of canagliflozin and its degradation products by HPLC with UV and MS detector was developed. The developed method was used to study the forced degradation of canagliflozin and to investigate the major degradation products resulting from exposure of canagliflozin to oxidative stress. Canagliflozin is a phenolic glycoside derivative and a glucose-sodium transporter 2 inhibitor that stimulates urinary glucose excretion by suppressing glucose reabsorption from the proximal tubule in the kidneys. Canagliflozin is used to control blood glucose levels in patients with type 2 diabetes. In an optimized method, an Agilent Poroshell 120 SB-Aq (2.1 × 100 mm, 2.7 µm) column was used and a mixture of buffer (10mM HCOOH adjusted with ammonium hydroxide to pH 3.5) and acetonitrile as a mobile phase. The method validation included testing of accuracy, repeatability, the limit of detection and quantification, linearity and linear dynamic range, the robustness of the method, and testing of sample stability. The limit of detection of the method was 8.9·10-5 mg ml-1 (2.0·10-7 mol l-1 ) and the limit of quantification was 3.0·10-4 mg ml-1 (6.8·10-7 mol l-1 ). At a concentration of 0.3 mg ml-1 , the repeatability (n = 7) was 0.17 % and 0.75 % for the retention time and the peak...

Type 2 diabetes mellitus (T2DM) carries a high prevalence in the United States and worldwide. Therefore, the number of medication classes being developed and studied has grown. The individualized management of diabetes is accomplished by evaluating a medication's efficacy, safety, and cost, along with the patient's preference and tolerance to the medication. Sodium glucose co-transporter 2 inhibitors are a new therapeutic class indicated for the treatment of diabetes and have a unique mechanism of action, independent of beta-cell function. The first agent approved by the Food and Drug Administration (FDA) was canagliflozin in March 2013. Two agents - dapagliflozin and empagliflozin - were FDA-approved in January and July 2014, respectively. A clear understanding of the new class is needed to identify its appropriate use in clinical practice. Members of the American College of Clinical Pharmacy Endocrine and Metabolism Practice and Research Network reviewed available literature regarding this therapeutic class. The article addresses the advantages, disadvantages, emerging role, and patient education for sodium glucose co-transporter 2 inhibitors. Key limitations for this article include limited access to clinical trial data not published by the pharmaceutical company and limited data on products produced outside the United States.

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Chronic kidney disease (CKD) is a worldwide health burden with increases risk of end-stage renal function if left untreated. CKD induced in the context of metabolic syndrome (MS) increases risks of hypertension, hyperglycemia, excess body fat and dyslipidemia. Our Centre previously generated a renin-dependent hypertensive/ type 1 diabetic mouse model and lead to the development of several signs associated with human diabetic kidney disease (DKD), however the extent and impact of dyslipidemia in this model remains unknown. We hypothesized that combining a high-fat diet (HFD) regimen onto the hypertensive/ diabetic phenotype would mimic features of MS induced-CKD in mice. An 8-week-old male genetically hypertensive mice (Lin+) were subjected to streptozotocin (STZ) intraperitoneal (i.p.) injections (50 mg/kg, 5 days consecutive) to induce hyperglycemia. Four-weeks later hypertensive/ diabetic mice (Lin+ mouse with induced beta cells death, also known as LinSTZ) were fed a 60% kCal HFD for 8 weeks. This study shows that HFD-fed LinSTZ mice developed less glomerular hypertrophy, scarring and albuminuria and hepatocytes fat accumulation at endpoint than regular-diet fed littermates. Moreover, antidiabetic drug Canagliflozin, dosed at 30 mg/kg body weight, showed reno-protection in the LinSTZ mice model. Taken together, our results show that LinSTZ mice fed a HFD did not lead to a more robust model of MS induced CKD. In fact, several indices of renal injury were reduced by feeding LinSTZ mice a HFD or treating them with Canagliflozin.

Yes / Recent clinical trials of the hypoglycaemic sodium-glucose co-transporter-2 (SGLT2) inhibitors, which inhibit renal glucose reabsorption, have reported beneficial cardiovascular outcomes. Whether SGLT2 inhibitors directly affect cardiovascular tissues, however, remains unclear. We have previously reported that the SGLT2 inhibitor canagliflozin activates AMP-activated protein kinase (AMPK) in immortalised cell lines and murine hepatocytes. As AMPK has anti-inflammatory actions in vascular cells, we examined whether SGLT2 inhibitors attenuated inflammatory signalling in cultured human endothelial cells. Incubation with clinically-relevant concentrations of canagliflozin, but not empagliflozin or dapagliflozin activated AMPK and inhibited IL-1β-stimulated adhesion of pro-monocytic U937 cells and secretion of IL-6 and monocyte chemoattractant protein-1 (MCP-1). Inhibition of MCP-1 secretion was attenuated by expression of dominant-negative AMPK and was mimicked by the direct AMPK activator, A769662. Stimulation of cells with either canagliflozin or A769662 had no effect on IL-1β-stimulated cell surface levels of adhesion molecules or nuclear factor-κB signalling. Despite these identical effects of canagliflozin and A769662, IL-1β-stimulated IL-6/MCP-1 mRNA was inhibited by canagliflozin, but not A769662, whereas IL-1β-stimulated c-jun N-terminal kinase phosphorylation was inhibited by A769662, but not canagliflozin. These data indicate that clinically-relevant canagliflozin concentrations directly inhibit endothelial pro-inflammatory chemokine/cytokine secretion by AMPK-dependent and -independent mechanisms without affecting early IL-1β signalling. / Project Grant (PG/13/82/30483 to IPS and TMP) and PhD studentships (FS/16/55/32731 and FS/14/61/31284 to DB and AS) from the British Heart Foundation and an equipment grant (BDA11/0004309 to IPS and TMP) from Diabetes UK. OJK was supported by a Scholarship from the Iraqi Ministry of Higher Education and Scientific Research. TAA was supported by a Libyan Ministry of Education PhD Studentship.