Increased Susceptibility of tumor cells at low concentrations of 5-Fluorouracil by blocking autophagy with chloroquine

• Grant number: 14/12459-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): September 01, 2014
• Effective date (End): August 31, 2015
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Ramon Kaneno
• Grantee: Bianca Francisco Falasco
• Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil

Abstract

The Colorectal Cancer (CRC) is the worldwide third most common type of cancer among men and the second among women, causing high rates of mortality and morbidity. Conventional treatment of CRC is the partial or total colectomy with pre-or postoperative chemotherapy. One of the major chemotherapeutic drugs used in the treatment of CRC is 5-Fluorouracil (5-Fu). Its administration in maximum tolerated dose (MTD) is able to promote tumor cell death, but also induces cytotoxic effects in normal tissues, causing among other effects, immunosuppression. This condition allows tumor resistance and recurrence of disease. Meanwhile, metronomic chemotherapy, with lower and more frequently doses administration, induces weaker adverse effects besides promoting immunomodulation. The main resistance mechanism of tumor cells is the autophagy, a mechanism for preserving cells from the recycling of organelles. Drugs such as chloroquine (CQ) can reduce cells autophagy capacity and potentiate the therapeutic effect of 5-Fu. Therefore, we hypothesized that the anti-autophagic action of chloroquine may potentiate the antitumor activity of ultralow concentrations of 5-FU and favor the establishment of a specific antitumor immune response. We aimed to test: a) if low concentrations of 5-FU induce autophagy in cells of human colon cancer HT-29 and HCT-116; b) if chloroquine interferes in the process and c) if the combination increases the immunogenicity of the cells.