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

• Published in: Journal of photochemistry and photobiology. B, Biology Biology, 2020-10, Vol.211, p.111992, Article 111992
• Main Authors: Franchi, Leonardo Pereira, de Freitas Lima, Jéssica Ellen Barbosa, Piva, Henrique Luis, Tedesco, Antonio Claudio
• Format: Article
• Language: English
• Subjects: A549 Cells; Aluminum - chemistry; Aluminum phthalocyanine chloride, cancer cell lines; Annexin V; Anticancer properties; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Benzoquinones - chemistry; Benzoquinones - pharmacology; Cancer; Cell cycle; Cell death; Cell Survival; Cell viability; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - radiation effects; DNA fragmentation; DNA repair; DNA-(Apurinic or Apyrimidinic Site) Lyase - antagonists & inhibitors; DNA-(Apurinic or Apyrimidinic Site) Lyase - genetics; Endonuclease; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Gene Expression Regulation - radiation effects; HeLa Cells; Humans; Indoles - chemistry; Indoles - pharmacology; Mitochondria; Mitochondria - radiation effects; Mortality; Nanoparticles - chemistry; Oxidation; Oxidation-Reduction; Oxidative stress; Oxidative Stress - radiation effects; Perturbation; Photochemotherapy; Photodynamic therapy; Photosensitizing Agents - chemistry; Photosensitizing Agents - pharmacology; Propionates - chemistry; Propionates - pharmacology; Proteins; Redox factor-1; Redox function, DNA repair; Redox reactions; Repair; Superoxide; Superoxides - chemistry; Toxicity; Tumor cell lines
• ISSN: 1011-1344; 1873-2682
• DOI: 10.1016/j.jphotobiol.2020.111992

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 (redox-function) 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 (~ 3.5×) 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 APE1's 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. •The APE1-protein presents a key role in cancer cells' response to PDT.•HeLa cells are overly sensitive to the combination of the molecule E3330 with PDT.•The APE1-protein level is downregulated when E3330 is combined with PDT.