Reversine exhibits antineoplastic activity in JAK2... - BV FAPESP
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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Reversine exhibits antineoplastic activity in JAK2(V)(617)(F)-positive myeloproliferative neoplasms

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Author(s):
Lima, Keli [1] ; Elias Godoy Carlos, Jorge Antonio [1] ; Alves-Paiva, Raquel de Melo [2] ; Vicari, Hugo Passos [1] ; de Souza Santos, Fabio Pires [2] ; Hamerschlak, Nelson [2] ; Costa-Lotufo, Leticia Veras [1] ; Traina, Fabiola [3] ; Machado-Neto, Joao Agostinho [1]
Total Authors: 9
Affiliation:
[1] Univ Sao Paulo, Biomed Sci Inst, Dept Pharmacol, Sao Paulo - Brazil
[2] Albert Einstein Hosp, Einsteins Teaching & Res Inst, Sao Paulo - Brazil
[3] Univ Sao Paulo, Dept Med Images Hematol & Clin Oncol, Ribeirao Preto Med Sch, Ribeirao Preto, SP - Brazil
Total Affiliations: 3
Document type: Journal article
Source: SCIENTIFIC REPORTS; v. 9, JUL 9 2019.
Web of Science Citations: 0
Abstract

JAK2/STAT signaling participates in the Ph-negative myeloproliferative neoplasms (MPN) pathophysiology and has been targeted by ruxolitinib, a JAK1/2 inhibitor. In the present study, the impact of ruxolitinib treatment on cytoskeleton-related genes expression was explored. In SET2 cells, AURKA and AURKB expression/activity were downregulated in a dose- and time-dependent manner by ruxolitinib. Reversine, a multikinase inhibitor selective for aurora kinases, reduced cell viability in a dose- and/or time-dependent manner in JAK2(V)(617)F cells. Reversine significantly increased apoptosis and mitotic catastrophe, and reduced cell proliferation and clonogenic capacity in SET2 and HEL cells. In the molecular scenario, reversine induced DNA damage and apoptosis markers, as well as, reduced AURKA and AURKB expression/activity. In SET2 cells, reversine modulated the expression of 32 out of 84 apoptosis-related genes investigated, including downregulation of antiapoptotic (BCL2, BCL2L1, and BIRC5) and upregulation of proapoptotic (BIK, BINP3, and BNIP3L) genes. Synergism experiments indicated that low dose of reversine had a potentiating effect under ruxolitinib treatment at low doses in SET2 cells. In summary, our exploratory study establishes new targets, related to the regulation of the cellular cytoskeleton, for potential pharmacological intervention in MPN. These findings indicate that AURKA and AURKB participate in the JAK2/STAT signaling pathway and contribute to the MPN phenotype. (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