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Preclinical study of a colchicine binding site tubulin inhibitor with potent anti-leukemia activity and low toxicity

Grant number: 17/14737-6
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): December 11, 2017
Effective date (End): December 10, 2018
Field of knowledge:Health Sciences - Medicine
Principal Investigator:José Andrés Yunes
Grantee:Nathalia Moreno Cury
Supervisor abroad: Sinisa Dovat
Home Institution: Centro Infantil de Investigações Hematológicas Dr Domingos A Boldrini (CIB). Campinas , SP, Brazil
Local de pesquisa : Penn State College of Medicine, United States  
Associated to the scholarship:14/08247-8 - Preclinical studies of novel inhibitors of DNA methyltransferase in acute leukemia, BP.DR

Abstract

Acute lymphoblastic leukemia (ALL) has an excellent cure rate, but 20% of patients still relapsed. Relapsed leukemia cells show a higher expression of membrane-associated ATP-binding cassette (ABC) transporters when compared to leukemic cells at diagnosis. Overexpression of ABC transporters decreases intracellular drug levels, consequently limiting drug cytotoxicity since they pump drug molecules off the cell. Discovery of new drugs and therapeutic targets can help to improve these rates. Microtubule inhibitors represent a group of promising compound in ALL treatment, since leukemic cells require intact microtubules for proper cell division. We have worked with an acylhydrazone, called compound #12, which exhibited strong anti-microtubule and anti-leukemia activities, in vitro. Besides, compound #12 is not a target of ABC transporters and showed very low in vivo toxicity. The aim of this project is to test compound #12 against xenograft models of high-risk ALL expressing the multidrug resistant (MDR)phenotype, characterizing its cellular mechanism(s) of action. The screening of the high risk ALL xenograft for the MDR phenotype will be performed, using the calceín exclusion assay. The anti-leukemia effect of compound #12 will be tested in comparison to vincristine, by measuring the presence of leukemia cells in peripheral blood, weight loss and survival in three high risk ALL xenografts with the MDR phenotype. Finally, the elucidation of compound #12' mechanisms of action in comparison to vincristine and colchicine will be done using gene expression analysis and functional validation of potential targets. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
CURY, NATHALIA MORENO; MUEHLETHALER, TOBIAS; ALBERTONI LARANJEIRA, ANGELO BRUNELLI; CANEVAROLO, RAFAEL RENATINO; ZENATTI, PRISCILA PINI; LUCENA-AGELL, DANIEL; BARASOAIN, ISABEL; SONG, CHUNHUA; SUN, DONGXIAO; DOVAT, SINISA; YUNES, ROSENDO AUGUSTO; PROTA, ANDREA ENRICO; STEINMETZ, MICHEL OLIVIER; FERNANDO DIAZ, JOSE; YUNES, JOSE ANDRES. Structural Basis of Colchicine-Site targeting Acylhydrazones active against Multidrug-Resistant Acute Lymphoblastic Leukemia. ISCIENCE, v. 21, p. 95+, NOV 22 2019. Web of Science Citations: 0.
CURY, NATHALIA MORENO; CAPITAO, REBECA MONIQUE; BORGES DE ALMEIDA, RENAN DO CANTO; ARTICO, LEONARDO LUIS; CORREA, JULIANA RONCHI; SIMAO DOS SANTOS, ERIC FRANCISCO; YUNES, JOSE ANDRES; DUARTE CORREIA, CARLOS ROQUE. Synthesis and evaluation of 2-carboxy indole derivatives as potent and selective anti-leukemic agents. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 181, NOV 1 2019. Web of Science Citations: 0.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.