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

Autor: Carlos JAEG; Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, São Paulo, SP, CEP 05508-900, Brazil., Lima K; Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, São Paulo, SP, CEP 05508-900, Brazil., Coelho-Silva JL; Department of Medical Images, Hematology and Clinical Oncology, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo, SP, Brazil., de Melo Alves-Paiva R; Einstein's Teaching and Research Institute, Albert Einstein Hospital, São Paulo, SP, Brazil., Moreno NC; Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil., Vicari HP; Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, São Paulo, SP, CEP 05508-900, Brazil., de Souza Santos FP; Einstein's Teaching and Research Institute, Albert Einstein Hospital, São Paulo, SP, Brazil., Hamerschlak N; Einstein's Teaching and Research Institute, Albert Einstein Hospital, São Paulo, SP, Brazil., Costa-Lotufo LV; Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, São Paulo, SP, CEP 05508-900, Brazil., Traina F; Department of Medical Images, Hematology and Clinical Oncology, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo, SP, Brazil., Machado-Neto JA; Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, São Paulo, SP, CEP 05508-900, Brazil. jamachadoneto@usp.br.
Jazyk: angličtina
Zdroj: Cellular oncology (Dordrecht) [Cell Oncol (Dordr)] 2020 Dec; Vol. 43 (6), pp. 1191-1201. Date of Electronic Publication: 2020 Aug 28.
DOI: 10.1007/s13402-020-00551-3
Abstrakt: 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 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.
Databáze: MEDLINE
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