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Evaluation of the relationship between energy fluence variation and cell death pathways induced by photodynamic therapy with methylene blue in breast tumors

Grant number: 19/09517-2
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): June 01, 2019
Effective date (End): May 31, 2020
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Ancély Ferreira dos Santos
Grantee:Gabriel Santos Arini
Home Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Breast cancer is a worldwide public health problem and even with a wide range of treatments, it is often associated with high morbidity. Thus, the development of therapeutic procedures that present equal or superior clinical results, and that present fewer side effects, is a field of research of fundamental interest. One of these alternatives is photodynamic therapy (PDT), which is based on the photooxidation of the biological material and involves the administration of photosensitizer (Ps) and its activation by the light at wavelength of maximum absorption compatible with the Ps used as well as the presence of oxygen. At the molecular level, PDT is capable of inducing multiple mechanisms of cell death, depending on the type of Ps and the irradiation protocol used. Among the several compounds that have been synthesized and tested as possible agents in PDT, methylene blue (MB) is efficient and inexpensive. Recent group results point towards the efficiency of methylene blue-mediated photodynamic therapy (MB-PDT) in the treatment of breast cancer. However, some inconsistencies related to the efficacy of PDT evidences the need for more in-depth studies on the parameters involved in it to be configured as a clinical treatment option. The molecular studies under development by our group on human mammary tissue models, both tumor and non-tumor, have contributed to the understanding of the dose-effect relationship and to the feasibility of an efficient protocol for the application of this therapy in the future. Our recent data point to the dependence of energy fluence (not just the final dose) on the cytotoxic effect of MB-PDT. In addition, it has been noted that this effect is cell type dependent. Preliminary results show that decreasing the irradiation time from 16 to 6 minutes, but maintaining the same final energy, resulted in a 75% decrease in the efficiency of MB-PDT in MCF-7 cells. In view of these findings, understanding how the time dependence of exposure influences the antioxidant response or the mechanism responsible for the cytotoxicity of the therapy can determine the success of the procedure, contributing to a better viability of the therapy. In this sense, the present project aims to clarify the relationship between irradiation time (maintaining the same dose of energy) and cellular response to MB-PDT. More specifically, we intend to evaluate the antioxidant response of the cell and the contribution of different mechanisms of death, such as apoptosis, necroptosis and ferroptosis in two different irradiation times. The project will be developed at the Institute of Chemistry of USP, in the laboratory of Molecular Mechanisms of Cytoprotection, coordinated by Professor Leticia Labriola. In addition, we counted on the collaboration of Professors Maurício da Silva Baptista, Bettina Malnic and Sayuri Miyamoto, of the Department of Biochemistry of the same institute. The project is original, feasible, since all techniques were previously standardized by the group, and promising, based on their preliminary results. The continuity of this study will provide fundamental information on the repercussion of the different parameters that must be controlled in order to increase the success of this promising therapy.