Reversine exerts cytotoxic effects through multiple cell death mechanisms in acute lymphoblastic leukemia
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ORIGINAL PAPER
Reversine exerts cytotoxic effects through multiple cell death mechanisms in acute lymphoblastic leukemia Jorge Antonio Elias Godoy Carlos 1 & Keli Lima 1 & Juan Luiz Coelho-Silva 2 & Raquel de Melo Alves-Paiva 3 & Natália Cestari Moreno 4 & Hugo Passos Vicari 1 & Fábio Pires de Souza Santos 3 & Nelson Hamerschlak 3 & Leticia Veras Costa-Lotufo 1 & Fabiola Traina 2 & João Agostinho Machado-Neto 1 Accepted: 22 July 2020 # International Society for Cellular Oncology 2020
Abstract 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 G2/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 γ-H2AX levels. In Namalwa cells, reversine modulated 25 out of 84 autophagy-related genes, including BCL2, BAD, ULK1, ATG10, IRGM and MAP1LC3B, 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. Keywords Acute lymphoblastic leukemia . Cell death . Aurora kinases . Reversine
Jorge Antonio Elias Godoy Carlos and Keli Lima contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13402-020-00551-3) contains supplementary material, which is available to authorized users. * João Agostinho Machado-Neto [email protected]
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Department of Medical Images, H
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