The redox function of apurinic/apyrimidinic endonuclease 1 as key modulator in photodynamic therapy

Author(s)

Franchi, Leonardo Pereira ; Barbosa de Freitas Lima, Jessica Ellen ; Piva, Henrique Luis ; Tedesco, Antonio Claudio

• Document type: Journal article
• Source: JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY; v. 211, p. 13-pg., 2020-10-01.

Abstract

Photodynamic therapy (PDT) is an anticancer modality depicting an induced oxidative stress as the mechanism of action that ultimately culminates in cell death. The apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a key protein promoting bad prognostic in several cancer types. APE1/Ref-1 is able to regulate cell response to oxidative stress by two basic protein activities, including a reduction-oxidation-function and a DNA repair-function. Therefore, the efficacy of anticancer therapies is negatively affected by APE1-overexpression. Thus, here it was evaluated the potential of APE1-chemical inhibitors as sensitizers for PDT in two different cancer cell lines (A549 and HeLa cells). Both functions of APE1 were addressed using E3330 (redoxfunction) and CRT0044876 (DNA repair-function) molecules. A detailed cytotoxicity screening (cell viability, cell cycle kinetics, mitochondrial perturbation, and cell death) indicated HeLa cells as extremely sensitive (similar to 3.5 x) to the combination of PDT with E3330 when compared to A549 cells. The treatment using PDT with E3330 induced downregulation of APE1 as detected by Western Blot. The APErs downregulation correlated to an increase of DNA fragmentation (17% and 66% in A549 and HeLa cells, respectively) and cell death rate (total: 24% and 74% in A549 and HeLa cells, respectively) characterized by annexin V and 7-AAD markers as well as a considerable difference in superoxide detected in mitochondria (29% and 78% in A549 and HeLa cells, respectively). This study definitively detected an increase in PDT efficacy when APE1's redox function is dysregulated by E3330. (AU)

• FAPESP's process: 17/14630-7 - The role of extracellular vesicles in photodynamic therapy of perihilar cholangiocarcinoma
• Grantee: Leonardo Pereira Franchi
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 13/50181-1 - Use of drugs containing nanocarriers with photosensitizers and/or other active compounds applied to cell therapy and treatment of central nervous system disorders
• Grantee: Antonio Claudio Tedesco
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 14/11870-9 - Sensitizing cancer cell lines to photodynamic therapy through inhibition of protein APE1
• Grantee: Leonardo Pereira Franchi
• Support Opportunities: Scholarships in Brazil - Post-Doctoral