Investigation of the effects of PARP and PLK1 co-inhibition against n MCF-7 and MDA-MB-231 breast cancer cell lines

Development with of the molecular biology, researchers have determined that the development of drugs that target DNA damage repair pathways is one of the effective ways to treat cancer. Because such targeted drugs not only show anti-cancer activity, but also increase the sensitivity of cancer cells to traditional chemotherapeutic drugs, especially drugs that kill cancer cells by damaging DNA. Small molecules serve as anti-cancer agents to overcome drug resistance and improve the prognosis and survival of cancer patients, thus offering potential new treatments for cancers. Due to their advantages in efficacy and safety compared with traditional chemotherapy drugs, targeted therapeutic drugs have become mainstream cancer treatments.Our thesis is based on identifying cellular components that provide a better understanding of the treatment responses of the PARP inhibitor olaparib and PLK1 inhibitor BI-2536 drugs in MCF-7 and MDA-MB-231 breast cancer cell lines, and understanding their molecular mechanisms in subsequent studies. For this purpose, we conducted studies using MCF-7 and MDA-MB-231 breast cancer cell lines to determine the effect of PLK1 activity on the survival of breast cancer cells, and the effect of olaparib and BI-2536 combination therapy on colony survival in MCF-7, U2OS and MDA-MB-231 breast cancer cells and its possible effects on cancer cell migration were investigated. Mono and combination treatments of olaparib and BI-2536 molecules in MCF-7 and MDA-MB-231 breast cancer cells expression levels of proteins in DNA damage, cell cycle and apoptotic signaling pathways were examined by Western blotting method. BRCA2 expression was blocked using RNA interference technology, and manipulation of BRCA2 gene expression was detected in MCF-7 and U2OS breast cancer cell lines by Western blotting analysis. Cell viability and colony survival were determined in BRCA2-effective and BRCA2-defective MCF-7 cells. In addition, the molecular interactions of olaparib and BI-2536 compounds with proteins were determined by molecular docking analyses. The results we obtained shows that the combination treatment of olaparib and BI-2536 molecules in MCF-7 and MDA-MB-231 breast cancer cells reduces the cell viability of breast cancer cells and suppresses their colony survival. It was determined that olaparib and BI-2536 combined treatment showed a synergistic cytotoxic effect in MCF-7 and MDA-MB-231 breast cancer cells, causing more DNA damage compared to the respective individual treatments. In conclusion, considering the increased PLK1, p53, p21, γH2AX, Nrf-2, Cyclin E, A and B1 expression and decreased HER-2, NF-κB and Cyclin D1 expression in breast cancer patients, PLK1 inhibition may increase the anti-cancer capacity of PARP inhibitors has been found to have potential.