AD80, a multikinase inhibitor, exhibits antineoplastic effects in acute leukemia cellular models targeting the PI3K/STMN1 axis

Autor(es)

Carlos, Jorge Antonio Elias Godoy ^[1] ; Lima, Keli ^[1] ; Costa-Lotufo, Leticia Veras ^[1] ; Leitao, Andrei ^[2] ; Machado-Neto, Joao Agostinho ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, Ave Prof Lineu Prestes 1524, BR-05508900 Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Med & Biol Chem Grp, Inst Chem Sao Carlos, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: INVESTIGATIONAL NEW DRUGS; v. 39, n. 4, p. 1139-1149, AUG 2021.
• Citações Web of Science: 0

Resumo

Despite the great advances in the understanding of the molecular basis of acute leukemia, very little of this knowledge has been translated into new therapies. Stathmin 1 (STMN1), a phosphoprotein that regulates microtubules dynamics, is highly expressed in acute leukemia cells and promotes cell cycle progression and proliferation. GDP366 has been described as a STMN1 and survivin inhibitor in solid tumors. This study identified structural GDP366 analogs and the cellular and molecular mechanisms underlying their suppressive effects on acute leukemia cellular models. STMN1 mRNA levels were higher in AML and ALL patients, independent of risk stratification (all p < 0.001). Cheminformatics analysis identified three structural GDP366 analogs, with AD80 more potent and effective than GSK2606414 and GW768505A. In acute leukemia cells, GDP366 and AD80 reduced cell viability and autonomous clonal growth in a dose- and/or time-dependent manner (p < 0.05) and induced apoptosis and cell cycle arrest (p < 0.05). At the molecular level, GDP366 and AD80 reduced Ki-67 (a proliferation marker) expression and S6 ribosomal protein (a PI3K/AKT/mTOR effector) phosphorylation, and induced PARP1 (an apoptosis marker) cleavage and gamma H2AX (a DNA damage marker) expression. GDP366 induced STMN1 phosphorylation and survivin expression, while AD80 reduced survivin and STMN1 expression. GDP366 and AD80 modulated 18 of the 84 cytoskeleton regulators-related genes. These results indicated that GDP366 and AD80 reduced the PI3K/STMN1 axis and had cytotoxic effects in acute leukemia cellular models. Our findings further highlight STMN1-mediated signaling as a putative anticancer target for acute leukemia. (AU)

• Processo FAPESP: 17/24993-0 - Investigação da participação de Stathmin 1 e da instabilidade dos microtúbulos no fenótipo de neoplasias hematológicas
• Beneficiário: João Agostinho Machado Neto
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 15/17177-6 - Abordagem integrada na prospecção sustentável de produtos naturais marinhos: da diversidade a substâncias anticâncer
• Beneficiário: Leticia Veras Costa Lotufo
• Modalidade de apoio: Auxílio à Pesquisa - Programa BIOTA - Temático
• Processo FAPESP: 18/15904-6 - Caracterização de inibidores de cisteíno proteases com atividade antineoplásica por meio de ensaios in silico, celulares e análise química
• Beneficiário: Andrei Leitão
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 18/19372-9 - Investigação do efeito de potenciais inibidores de Stathmin 1 obtidos através de quimioinformática no fenótipo das leucemias agudas
• Beneficiário: Jorge Antonio Elias Godoy Carlos
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 19/23864-7 - Análise compreensiva de dados genômicos para identificação e validação de novos alvos terapêuticos envolvidos na regulação de citoesqueleto celular em Leucemias agudas
• Beneficiário: João Agostinho Machado Neto
• Modalidade de apoio: Auxílio à Pesquisa - Regular