The effects of temozolomide and resveratrol on stress proteins in glioma cells

Cancer is one of the leading diseases that cause human death. In vitro studies are very important to understand the molecular mechanisms of tumor formation in cancer research. Even though brain tumor is a quite rare in the population, glioblastoma is the most common and aggressive malignant brain tumor. These types of tumors are highly resistant to chemotherapy and the average life expectancy is up to 16 months after diagnosis. Expression of stress proteins (Heat Shock Proteins, HSP) are known to increase in many types of cancer and they are suitable biomarkers for the treatment of cancer. Heat shock proteins are closely associated with cancer cell proliferation, differentiation, metastasis and death. In addition, in recent articles, it was found that heat shock proteins play a role in the mechanism of resistance to certain drugs used in cancer. Overexpression of these proteins in brain tumors has made them major anticancer targets. For this purpose, the development of HSP inhibitors that can be used in cancer treatment has become important. Temozolomide, an alkylating agent, is a chemotherapy drug used to treat glioblastoma. Although it is widely used in patients with brain tumor, because of the resistance of glioblastoma to this drug, its therapeutic effect is very limited. Resveratrol, a natural polyphenolic molecule, has anticarcinogenic potential and is an potent compound to prevent cancer. In recent years, there have been studies that combined treatment methods using natural compounds and chemical drugs show significantly improved results for drug efficacy. In this thesis, it was aimed to investigate the molecular mechanisms of temozolomide and resveratrol applied to U-87 MG human glioma cells by suggesting hypothesis that resveratrol may increase the sensitivity of glioblastoma cells to treatment with temozolomide. In order to evaluate the effectiveness of the combined applications, in vitro experiments were performed at the cell, protein and DNA levels (cytotoxic, immunological apoptotic and Comet analyzes, as well as the determination studies of intracellular reactive oxygen species, reduced glutathione and protein carbonyl levels). At the end of these comprehensive experiments, it was shown that the combined therapy of resveratrol with temozolomide suppressed HSPs and induced apoptosis in glioma cells. The same combination caused a significant increase in DNA breaks and intracellular reactive oxygen species as an indicator of oxidative stress, but no statistically significant change in protein carbonyls and glutathione levels compared to control. In conclusion, resveratrol combined with temozolomide increased drug efficacy in glioma cells. There was no negative effects in HEK 293 cells used as control cells. The findings of the thesis showed that TMZ and RSV combined treatment strategy for glioma patients may be more effective.