Screening of inhibitory molecules for human peroxiredoxin II, seeking treatment for Acute Lymphoid Leukemia (ALL)

Abstract

The National Cancer Institute (INCA) estimates that in 2014 there were about 11,500 new pediatric cancer cases, and <25% should be represented by Acute Lymphocytic Leukemia (ALL). The protocols for treatment are composed of combinations of various chemotherapeutic agents, including low molecular weight molecules that interfere with cell growth, such as asparaginase and cyclophosphamide. However, all chemotherapeutic agents used in the treatment of ALL lead to various side effects such as mutagenicity, teratogenicity, cytotoxic effects and allergies, with an urgent need for new drugs with reduced side effects. Recent studies have placed as targets for drugs enzymes involved in the breakdown of Reactive Oxygen Species (ROS), especially hydrogen peroxide (H2O2). It has been demonstrated that tumor cells the peroxidase expression is increased in order to maintain it in appropriate levels of growth and avoid apoptosis. In mammals, peroxidase called peroxiredoxin II (PrxII) appears to play a critical role in progression and maintenance of tumor cells and has been demonstrated that this enzyme has high levels of expression in neoplastic cells while its inhibition can make tumor cells more susceptible to treatment with radiotherapy or induce cell differentiation in tumor cells. Recently it was shown that a natural diterpenoid, Adenanthin (Adn), is capable of inhibiting quite effectively cell growth in vitro and in vivo of acute myeloid leukemia cells acting on this enzyme. However, there is no information of their effects on acute lymphocytic leukemia. The project aims to evaluate inhibitory effects on human PrxII from <90 isolated molecules on previous projects, including those similar to Adn, derived from the Brazilian biota. Evaluation of inhibition will be performed using enzymatic activity assays (FOX, NADPH oxidation and ferritiocianate) and structural changes of PrxII in the presence of ligands that show inhibitory activity will be evaluated by circular dichroism and size exclusion chromatography. We believe that the results of this project are subject to publication in journals of international prestige, as well as being patentable. (AU)