Pharmacological inhibition of autophagy and possible increase of anti-leukemic effects of cytarabine/idarubicin in acute myeloid leukemia

• Grant number: 17/19542-9
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: December 01, 2017
• End date: November 30, 2018
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Claudia Bincoletto Trindade
• Grantee: Larissa Gonçalves Bueno
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

The treatment used in acute myelogenous leukemia (AML) therapy involves the combination of cytarabine / idarubicin or daunorubinin. This treatment achieves a cure rate of 35-40% in patients less than 60 years of age, and 5-15% in older patients, since many individuals recur in a short time, which often results in low cure percentages. In this context, research involving strategies to improve the response of leukemic patients to current therapy should be encouraged not only to decrease systemic toxicity, as the increased myelosuppression with significant increases in infections, but also to improve rates of complete remission for a longer period of time. Recently, studies indicate that autophagy is dysregulated in leukemias, as it promotes the survival of leukemic cells, suggesting that their inhibition may become an interesting pharmacological target. Therefore, this project aims to understand the possible participation of autophagy, through its pharmacological inhibition with chloroquine (CQ), which will be associated with standard treatment with cytarabine / idarubicin (Ara-C / Ida). We will use as model of LMA leukemic cells U937 and HL60. Cell death studies will be performed using the labeling of cells treated with propidium iodide (PI) and annexin V / FITC / PI and cell differentiation will be assessed using differentiation markers for CD11b (monocytes) and CD15 (granulocytes). The study of the proteins involved in autophagy (LC3II and p62) will be performed by Western blotting. Throughout the period of this scientific initiation, the student will be coordinated by the post-doctoral student Dr. Caroline Palmeira dos Santos. (AU)