Date

2016

Author

Durukan, Özlem

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Prostate cancer is the most common cancer type both in developed and developing countries. Since 2015, it has been seen as one of the main cause of death in males, both in the world and in our country. Current therapeutic approaches for prostate cancer generally have variable efficiency, develop metastasis and drug resistance, and have high toxicity to normal tissues. Hence, the searching for more effective strategies with moderate or any adverse effects for the chemopreventive intervention of those cancers remains one of the important issues in cancer research. Prostate cancer incidence and mortality vary dramatically by geographical location. Both are higher in developed countries. Some attribute this to westernized lifestyles of high energy diets and limited physical activity with consequent obesity. This dramatic increase in the incidence of cancer in overweight population suggests that there is a correlation between obesity and cancer. As a matter of fact, epidemiological and experimental research indicates that men with abdominal obesity is a risk factor for prostate cancer. Because in the case of obesity, people store plenty of glucose. Thus, cancer cells are more easily and quickly divide. According to this information, our aim in this study was reducing cell proliferation by reducing the blood glucose amount that passes from hepatic tissues by using metformin, a Type2 diabetes drug, hence provide the induction of cell death by creating oxidative stress in cells. Cisplatin, a cell division and growth inhibiting agent, is widely used in the treatment of prostate cancer. Cisplatin binds to DNA and forms a DNA adduct. This adduct cause the death of cancer cells by inhibiting transcription and or replication. Despite the high efficiency of cisplatin on prostate cancer treatment not only nephrotoxicity, neurotoxicity and gastrointestinal irritability but also azoospermia, oligospermia and infertility on reproductive age restrict the use of cisplatin. In order to reduce the side effects of cisplatin, combination therapy with other agents has been the focus of scientists in recent years. Considering the inducer effect of metformin, a type2 diabetic drug, on antiproliferative and apoptotic pathways it can provide a complementary treatment with antineoplastic agents, including cisplatin. GST family enzymes function in the detoxification of xenobiotics, including drugs. Becide, recently it is understood that GST s also function on cell proliferation and death that controls signal transduction. Carcinogenesis, differentiation, growth and important impact on drug resistance and cell death serve GST s as an important drug targets. GST family is also involved in prostaglandin, steroid and leukotriene biosynthesis. In addition, to determination of GTSP protein and gene expression to investigate the effect of combined treatment on the role of androgen synthesis, expression of CYP17A1 enzyme was determined in the cell lines. Furtermore, the effect of this combined treatment on hexokinase enzyme which plays an important role in the glycolysis pathway was investigated. Dose response of this combined therapy and cytotoxic effect of those drugs were measured by Alamar Blue assay. The effects of cisplatin and metformin on proliferation of cancer cell lines were detected by colony formation assay. Also, the effects of drugs on CYP17A1 GSTP and Hexokinase II enzymes will be detected by protein and mRNA expressions by using Western-Blot and qRTPCR techniques, respectively. IC50 value of cisplatin was determined as 17µM for LNCaP and 30 µM for PC3 cell line. The cell proliferation results showed that, metformin potentiates the antiproliferative effect of cisplatin both in LNCaP and PC3 cell lines. However, according to Western-blot and qPCR analysis, this reduction can not be blamed by GSTP enzymes. Expression of GSTP enzyme increased in direct proportion to dose of metformin. At this point, metformin may antagonize the cisplatin apoptotic effect through suppression of oxidative stress in prostate cancer cells. On the other hand, cisplatinmetformin drug combination significantly decreased the CYP17A1 protein expressions in PC3 cell lines. Furthermore, Hexokinase II mRNA expressions are significantly decrease in a dose dependent manner. In the treatment of cancer, which is frightening diseases of our century, combined therapy of diabetes based drugs with chemotherapeutic drugs will be helpful not only to reduce the toxicity of the of cisplatin, but also to reduce the cost.  

Subject Keywords

Cisplatin., Apoptosis., Metformin., Cell death., Cytochromes., Prostate

URI

http://etd.lib.metu.edu.tr/upload/12620547/index.pdf 
https://hdl.handle.net/11511/25985

Collections

Graduate School of Natural and Applied Sciences, Thesis