PROGNOSTIC VALUE OF HORMONE RECEPTOR STATUS AND CLINICAL SIGNIFICANCE OF GLUTATHIONE IN OVARIAN CANCER

Abstract

Background. In the structure of female oncology, ovarian cancer ranks eighth among other diseases. Among the causes of death, it ranks seventh among all cancer diseases. In Ukraine, the mortality rate is 9.4 per 100,000 female population. Annually, 24.6% of newly diagnosed ovarian cancer die in Ukraine.

Glutathione is an antioxidant that protects the cell from the toxicity of reactive oxygen species. Data have shown that glutathione may play a role in malignancies, including ovarian cancer, and thus we sought to determine the clinical significance of glutathione and the effects of erastin (a glutathione synthesis inhibitor) in ovarian cancer.

Materials and methods. Immunohistochemical studies of protein expression were performed on parallel sections using monoclonal antibodies: against estrogen receptors – clone 1D5, against progesterone receptors – clone PgR636. The EnVision system (DakoCytomation) was used for protein visualization. Ovarian cancer tissues were taken from 41 patients, and the level of glutathione in cancer tissues was determined. Survival curves were performed using the Kaplan-Meier method and evaluated using the log-rank test. A multivariate Cox proportional hazard regression model was performed to identify an independent factor affecting the prognosis of patients with ovarian cancer. The effect of erastin in vitro was studied using ovarian cancer cell lines of different sensitivities. Cell viability, glutathione levels and (cytosolic and lipid) production of reactive oxygen species were assessed.

Results. The dependence of the expression of steroid hormone receptors on the degree of malignancy of ovarian cancer was revealed, namely, in patients with ovarian cancer of a high degree of malignancy, there is a significant decrease in the expression of estrogen receptors compared to patients whose tumors are of a low degree of malignancy. Patients with high tumor glutathione levels had lower progression-free survival and overall survival compared to patients with low glutathione levels. Tumor glutathione levels were independent prognostic factors for progression-free survival and overall survival. Baseline glutathione levels were important to assess sensitivity to erastin. Glutathione levels were important to assess sensitivity to erastin. A decrease in the level of glutathione increased the levels of reactive oxygen species, which caused cell death.

Conclusions. High tumor glutathione levels were found to be significantly associated with poor prognosis independent of other factors in ovarian cancer. Erastin induces the death of ovarian cancer cells in vitro depending on the level of intracellular glutathione. Tumor glutathione can be a prognostic biomarker of survival, and erastin should be studied as a new drug in the complex therapy of ovarian cancer.