Effect of chloroquine and 5- fluorouracil association on the immunogenicity of tumor cell exosomes

• Grant number: 14/12548-3
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): January 01, 2015
• Effective date (End): July 31, 2015
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Graziela Gorete Romagnoli
• Grantee: Marina Melo de Almeida
• Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil

Abstract

The Maximum Tolerated Doses (MTD) schedule of chemotherapy may cause toxic effects in cancer patients, while the interval required between drug administration can allow the development of drug-resistant cells. Alternatively, some centers employ the metronomic chemotherapy regimen, based on the continuous use of lower doses of antitumor agents, in order to maintain effective serum levels of drugs. However, drug resistance is also observed in patients under this regimen, being the autophagy one of the mechanisms involved in this process, allowing tumor cells to adapt to environmental changes. Recent studies have shown that chloroquine (CQ), an anti-malarial drug, decreases autophagy in tumor cells, consequently increasing their susceptible to chemotherapeutic 5-fluorouracil (5-FU). Since CQ inhibits the fusion of lysosomes with intracytoplasmic vesicles, thus interfering with the degradation pathway, we believe that the secretory route could be favored by exposure to drugs, enhancing the secretion of exosomes (Exo) by tumor cells, as well as preserving the proteins associated to exosomes. Exo are nanovesicles of endocytic origin, present in body fluids and are involved with intercellular communication. Exo from tumor cells are antigens sources and are able to induce antitumor responses. Therefore, the aim of this study is to verify if the combination of low dose of 5-FU with CQ can increase the release of Exo by tumor cells, conferring them enhanced immunogenicity. With this goal, we will verify if such Exo change the human monocytes phenotype, inducing increased expression of markers involved in the lymphocyte response.