Effects of Jak2 type 1 inhibitors NVP-BSK805 and NVP-BVB808 on Jak2 mutation-positive and Bcr-Abl-positive cell lines.

Abstract:

:Janus kinases are critical components of signaling pathways that regulate hematopoiesis. Mutations of the non-receptor tyrosine kinase JAK2 are found in many BCR-ABL-negative myeloproliferative neoplasms. Preclinical results support that JAK2 inhibitors could show efficacy in treating chronic myeloproliferative neoplasms. JAK2 has also been postulated to play a role in BCR-ABL signal transduction. Therefore, inhibitors of JAK2 kinases are turning into therapeutic strategies for treatment of chronic myelogenous leukemia (CML). In this study, the effects of two novel JAK2 inhibitors, NVP-BSK805 and NVP-BVB808, have been investigated in cell lines expressing either BCR-ABL or mutant JAK2. Possible synergies between NVP-BSK805/NVP-BVB808 and the kinase inhibitors imatinib and nilotinib were assessed. Proliferation and apoptosis tests with both substances showed response in the following cell lines: CHRF-288-11, SET-2 and UKE-1. All BCR-ABL-positive cell lines showed some reduction in proliferation, but with half-maximal growth-inhibitory values >1 µM. Combination of the JAK2 inhibitors with imatinib and nilotinib showed no significant additive or synergistic effects, although all BCR-ABL-positive cell lines responded well to both CML therapeutic agents. Interestingly, it seemed that the combination of imatinib with NVP-BSK805 had a protective effect on the cells. Combination treatment with nilotinib did not show this effect.

journal_name

Acta Haematol

journal_title

Acta haematologica

authors

Ringel F,Kaeda J,Schwarz M,Oberender C,Grille P,Dörken B,Marque F,Manley PW,Radimerski T,le Coutre P

doi

10.1159/000356784

subject

Has Abstract

pub_date

2014-01-01 00:00:00

pages

75-86

issue

1

eissn

0001-5792

issn

1421-9662

pii

000356784

journal_volume

132

pub_type

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