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Reversine Exhibits Antineoplastic Activity in JAK2

Reversine Exhibits Antineoplastic Activity in JAK2

Keli Lima, Jorge Antonio Elias Godoy Carlos, Raquel de Melo Alves-Paiva, Hugo Passos Vicari, Fábio Pires de Souza Santos, Nelson Hamerschlak, Leticia Veras Costa-Lotufo, Fabiola Traina, João Agostinho Machado-Neto

Sci Rep. 2019 Jul 9;9(1):9895.

PMID: 31289316

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP656820325	Reversine		656820-32-5	Price

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