The effect of cyclin -dependent kinase 4 and 6 inhibition on radiosensitivity in breast cancer lines

Cancer is a multi-step process involving metabolic and behavioral changes leading to excessive and untimely proliferation of cells. It is a disease with high incidence and mortality. Although breast cancer is the most common type of cancer in women, it is the leading cause of cancer-related deaths after respiratory-related cancers. Today, although the survival rates of breast cancer patients have increased after treatment, the mortality rate of breast cancer does not change. Therefore, testing of new treatment methods is of great importance for breast cancer. Breast cancer; luminal A, luminal B, HER-2, basal and normal breast are divided into five groups. The subtype that requires the most therapeutic improvements is luminal-B breast cancer, where therapeutic resistance is common. Many studies have suggested that luminal-B breast cancer is relatively insensitive to endocrine therapy, chemotherapy, and radiotherapy compared to other types of breast cancer. Radiotherapy is one of the basic stones in the treatment of breast cancer. But breast tumors can gain radiation resistance; because they have irregular G1 / S phase cell cycle mechanisms.The irregular cell cycle contributes to uncontrolled cell proliferation, resulting in cancer formation. The key regulator of the G1-S transition is the cyclin D-CDK4 / 6-INK4-Rb pathway. Because of the importance of CDK4 / 6 activity in regulating cell proliferation and the mechanisms by which this pathway has been activated in cancer, selective inhibition of CDK4 / 6 inhibitors has emerged as an attractive treatment strategy. In cancer treatment, specific targeting of G1 stage of the cell cycle may be a suitable approach. Targeting the G1 phase will block the first step of the cell cycle, so cell division will also be blocked. Palbociclib is clinically the most advanced CDK4 / 6 inhibitor. The aim of our study; When palbociclib is applied together with radiotherapy, it is possible to show that the cancer cells become radiation sensitive by eliminating the radiation resistance. In our study we designed an experimental in vitro study on breast cancer cell lines. In this study, human breast cancer cell model MCF-7, non-tumorigenic breast epithelial cell MCF-10A and breast cancer stem cells were used. The cytotoxic effect of PD-0332991 in MCF-7, MCF-10A and MKKH was investigated. Clonogenic analyzes were performed to examine the efficacy of agents such as radiation and drugs on the survival and proliferation of cells. In MCF-7 and MKKH cells, colony formation occurred after administration of PD-0332991, radiation and combinations. The clonogenic analysis of PD-0332991, 4 gray radiation and combination therapies was performed and plate images were obtained and colony mean and plating efficiency, percentage survival fraction were determined. In MCF-10A cells, colony formation did not occur after administration of PD-0332991, radiation and combination therapy. In our study; We found that MCF-7 cells were more sensitive to PD-0332991. Palbociclib alone and in MCF-7 cells alone and radiation therapy alone significantly inhibited the formation of colonies. However, when we combined the two treatments, the survival rate was the lowest. These results led us to the combination therapy for MKKH and MCF-7 cells; showed that the drug alone and the radiographic sensitivity of PD0332991 göster alone increased. The expression changes of CCND1, CDKN1A, CDKN2A, CDC25A, WEE1, CHEK1 genes were investigated. The expression of WEE1 and CHEK1 genes decreased. Inhibition of WEE1 has made cells susceptible to radiation-induced cell death. We can predict that inhibition of CHEK1 leads cells to apoptosis. Increased levels of CDKN1A and CDKN2A suggest that cells will be dragged to aging after treatment. The results will be a resource for further studies to be planned, and will be effective in planning new strategies for cancer treatment.