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Reversine exhibits antineoplastic activity in JAK2V617F-positive myeloproliferative neoplasms.
Sci Rep 2019; 9(1):9895SR

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 JAK2V617F 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.

Authors+Show Affiliations

Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo, São Paulo, Brazil.Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo, São Paulo, Brazil.Einstein's Teaching and Research Institute, Albert Einstein Hospital, São Paulo, Brazil.Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo, São Paulo, Brazil.Einstein's Teaching and Research Institute, Albert Einstein Hospital, São Paulo, Brazil.Einstein's Teaching and Research Institute, Albert Einstein Hospital, São Paulo, Brazil.Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo, São Paulo, Brazil.Department of Medical Images, Hematology and Clinical Oncology, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo, Brazil.Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo, São Paulo, Brazil. jamachadoneto@usp.br.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31289316

Citation

Lima, Keli, et al. "Reversine Exhibits Antineoplastic Activity in JAK2V617F-positive Myeloproliferative Neoplasms." Scientific Reports, vol. 9, no. 1, 2019, p. 9895.
Lima K, Carlos JAEG, Alves-Paiva RM, et al. Reversine exhibits antineoplastic activity in JAK2V617F-positive myeloproliferative neoplasms. Sci Rep. 2019;9(1):9895.
Lima, K., Carlos, J. A. E. G., Alves-Paiva, R. M., Vicari, H. P., Souza Santos, F. P., Hamerschlak, N., ... Machado-Neto, J. A. (2019). Reversine exhibits antineoplastic activity in JAK2V617F-positive myeloproliferative neoplasms. Scientific Reports, 9(1), p. 9895. doi:10.1038/s41598-019-46163-2.
Lima K, et al. Reversine Exhibits Antineoplastic Activity in JAK2V617F-positive Myeloproliferative Neoplasms. Sci Rep. 2019 Jul 9;9(1):9895. PubMed PMID: 31289316.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Reversine exhibits antineoplastic activity in JAK2V617F-positive myeloproliferative neoplasms. AU - Lima,Keli, AU - Carlos,Jorge Antonio Elias Godoy, AU - Alves-Paiva,Raquel de Melo, AU - Vicari,Hugo Passos, AU - Souza Santos,Fábio Pires de, AU - Hamerschlak,Nelson, AU - Costa-Lotufo,Leticia Veras, AU - Traina,Fabiola, AU - Machado-Neto,João Agostinho, Y1 - 2019/07/09/ PY - 2018/12/19/received PY - 2019/06/21/accepted PY - 2019/7/11/entrez PY - 2019/7/11/pubmed PY - 2019/7/11/medline SP - 9895 EP - 9895 JF - Scientific reports JO - Sci Rep VL - 9 IS - 1 N2 - 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 JAK2V617F 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. SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/31289316/Reversine_exhibits_antineoplastic_activity_in_JAK2V617F-positive_myeloproliferative_neoplasms L2 - http://dx.doi.org/10.1038/s41598-019-46163-2 DB - PRIME DP - Unbound Medicine ER -