Reversine exerts cytotoxic effects through multiple cell death mechanisms in acute lymphoblastic leukemia

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Elias Godoy Carlos, Jorge Antonio ^[1] ; Lima, Keli ^[1] ; Coelho-Silva, Juan Luiz ^[2] ; Alves-Paiva, Raquel de Melo ^[3] ; Moreno, Natalia Cestari ^[4] ; Vicari, Hugo Passos ^[1] ; de Souza Santos, Fabio Pires ^[3] ; Hamerschlak, Nelson ^[3] ; Costa-Lotufo, Leticia Veras ^[1] ; Traina, Fabiola ^[2] ; Machado-Neto, Joao Agostinho ^[1]

Afiliação do(s) autor(es)

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

^[2] Univ Sao Paulo, Dept Med Images Hematol & Clin Oncol, Ribeirao Preto Med Sch, Sao Paulo, SP - Brazil

^[3] Albert Einstein Hosp, Einsteins Teaching & Res Inst, Sao Paulo, SP - Brazil

^[4] Univ Sao Paulo, Inst Biomed Sci, Dept Microbiol, Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: CELLULAR ONCOLOGY; v. 43, n. 6 AUG 2020.
• Citações Web of Science: 0

Resumo

Purpose Acute lymphoblastic leukemia (ALL) is an aggressive hematological cancer with limited therapeutic options for adult patients. Aurora kinases have drawn attention as potential targets in hematological neoplasms due to their high expression and biological functions. Aurora kinase A (AURKA) and AURKB are essential for a successful mitosis, acting in spindle mitotic organization and cytokinesis. Reversine is a synthetic purine analog that acts as a multi-kinase inhibitor with anti-neoplastic activity by targeting AURKA and AURKB. Methods ALL patient gene expression data were retrieved from the Amazonia! database. For functional assays, Jurkat (T-ALL) and Namalwa (B-ALL) cells were exposed to increasing concentrations of reversine and submitted to various cellular and molecular assays. Results We found that AURKB expression was higher in ALL patient samples compared to normal lymphocytes (p < 0.0001). The ALL cell lines tested displayed aberrant AURKA and AURKB expression. In Jurkat and Namalwa cells, reversine reduced cell viability in a dose- and time-dependent manner (p < 0.05). Reversine also significantly reduced the viability of primary ALL cells. Reversine induced apoptosis and autophagy, and reduced cell proliferation in both cell lines (p < 0.05). Mitotic catastrophe markers, including cell cycle arrest at G(2)/M, increased cell size and DNA damage, were observed upon reversine exposure. Short- and long-term treatment with reversine inhibited autonomous clonogenicity (p < 0.05). At the molecular level, reversine reduced AURKB activity, induced SQSTM1/p62 consumption, and increased LC3BII and gamma-H2AX levels. In Namalwa cells, reversine modulated 25 out of 84 autophagy-related genes, includingBCL2,BAD,ULK1,ATG10,IRGMandMAP1LC3B, which indicates that reversine acts by initiating and sustaining autophagy signals in ALL cells. Conclusions From our data we conclude that reversine reduces the viability of ALL cells by triggering multiple cell death mechanisms, including apoptosis, mitotic catastrophe, and autophagy. Our findings highlight reversine as a potential anticancer agent for ALL. (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: 18/19372-9 - 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