THE EFFECT OF PKI-402 ON RADIATION AND CISPLATIN RESISTANCE IN LUNG CANCER STEM CELL LINE
Project no. 1122 · Status: Kapanmış · 2018
Summary
Lung cancer is considered a pandemic with major financial and social problems. It is estimated to be responsible for approximately 1.59 million deaths (19.4% of all cancers) in the world. Radiotherapy (RT) is one of the most important strategies that use ionizing radiation (IR) to kill cancer cells and shrink the tumor. Approximately 50% of all cancer patients receive RT alone or in combination with surgery and/or chemotherapy. Treatments fail because of radio / chemo resistance and disease recurrence. The reason for this is associated with the existence of cell populations with features such as self-renewal and differentiation, known as cancer stem cells (CSC). It is thought that the active and aberrant signal pathways in particular are the key points in the radio and chemo resistance of these cells. PI3K/Akt/mTOR is a prototypical pathway that is activated in many cancer types, including lung cancer. PKI-402 - potent dual pan PI3K / mTOR inhibitor targeting PI3K? / ß / ? / ? and mTOR as well as potent inhibitor for PI3K? mutants E545K and H1047R. It also has the potential to inhibit AKT phosphorylation. It is thought that AKT is activated after treatment and plays a major role in relapses. In our study, the combined effects of this active substance with cisplatin and IR on the lung cancer stem cell line (LCSC) were investigated. According to the findings, when PKI-402 and cisplatin are used in combination, it has been observed that it is effective at lower doses than the cytotoxic dose applied in the use of PKI-402 or cisplatin alone. Then, by applying this combination dose in combination with IR, clonogenic survival, DNA double strand break (DSB) analysis, cell cycle and apoptosis analysis were performed. According to the data obtained, the treatments caused significant changes in DSB values compared to the control, causing significant G2/M arrest, and it was observed that this arrest resulted in apoptotic cell death.