Sensitizing cancer cell lines to photodynamic therapy through inhibition of protein APE1

Abstract

This project is going to use a combination of two tools of different approaches to kill cancer cell lines. The first tool is photodynamic therapy (PDT) which has the induction of cell death by apoptosis/necrosis and autophagy processes as the greater biological effect. The second approach is going to focus on the use of chemicals and siRNA to inhibit APE1 protein. APE1 is a key protein in the mechanism of base excision repair (BER), and also act as an important co-activator of transcription factors such as P53 which is a multifunctional regulator involved in proliferation and cell death. We expect that the inhibition of APE1 sensitizes cancer cell lines to treatment with photodynamic therapy. We are going to characterize the cellular and molecular events induced by the combination of these treatments. Among the cellular events we hope to evaluate the induction of cell death by apoptosis, necrosis and autophagy as well as changes in the cell cycle progression. We also expect to understand the molecular mechanisms resulting from the combined treatment aiming to characterize oxidative stress, mitochondrial stress and DNA damage. Our main hypothesis is the effective cell death induction on combination treatment (PDT + APE1 inhibition) compared to single treatments (PDT vs. APE1 inhibition). Thus these results will provide a proof of concept to support the idea that inhibition of DNA repair pathways and cell signaling can increase the efficiency of PDT in cancer treatment. (AU)