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

Author(s):Show less -

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]

Affiliation

^[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

• Document type: Journal article
• Source: CELLULAR ONCOLOGY; v. 43, n. 6 AUG 2020.
• Web of Science Citations: 0

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 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)

• FAPESP's process: 17/24993-0 - Investigation of Stathmin 1 and microtubule instability in phenotype of hematological neoplasms
• Grantee: João Agostinho Machado Neto
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/17177-6 - Integrative approach on the sustainable prospection of marine natural products: from diversity to anticancer compounds
• Grantee: Leticia Veras Costa Lotufo
• Support Opportunities: BIOTA-FAPESP Program - Thematic Grants
• FAPESP's process: 18/19372-9 - Investigation of the effect of potential Stathmin 1 inhibitors obtained by chemoinformatics on the phenotype of acute leukemias
• Grantee: Jorge Antonio Elias Godoy Carlos
• Support Opportunities: Scholarships in Brazil - Master