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Title: Anti-myeloma effects of ruxolitinib combined with bortezomib and lenalidomide: A rationale for JAK/STAT pathway inhibition in myeloma patients
Authors: de Oliveira, Mariana B. [UNIFESP]
Fook-Alves, Veruska L. [UNIFESP]
Eugenio, Angela I. P. [UNIFESP]
Fernando, Rodrigo C. [UNIFESP]
Sanson, Luiz Felipe G. [UNIFESP]
de Carvalho, Mariana F. [UNIFESP]
Braga, Walter M. T. [UNIFESP]
Davies, Faith E.
Colleoni, Gisele W. B. [UNIFESP]
Keywords: Multiple myeloma
Small molecule inhibitor
Issue Date: 2017
Publisher: Elsevier Ireland Ltd
Citation: Cancer Letters. Clare, v. 403, p. 206-215, 2017.
Abstract: JAK proteins have been linked with survival and proliferation of multiple myeloma (MM) cells
therefore, JAK inhibition could be a therapeutic strategy for MM. We evaluated JAK1 and JAK2 expression in MM patients and the effects of JAK/STAT pathway inhibition on apoptosis, cell cycle, gene and protein expression in RPMI-8226 and U266 MM cell lines. 57% of patients presented overexpression of JA1C2 and 27%, of JAK1. After treatment with ruxolitinib and bortezomib, RPMI-8226 and U266 presented 50% of cells in late apoptosis, reduction of anti-apoptotic genes expression and higher number of cells in SubGO phase. Co-culture with stromal cells protected RPMI-8226 cells from apoptosis, which was reversed by lenalidomide addition. Combination of ruxolitinib, bortezomib and lenalidomide induced 72% of cell death, equivalent to bortezomib, lenalidomide and dexamethasone, combination used in clinical practice. Many JAK/STAT pathway genes, after treatment, had their expression reduced, mainly in RPMI-8226, with insignificant changes in U266. In this scenario, JAK/STAT pathway could pose as a new therapeutic target to be exploited, since it is constitutively active and contributes to survival of MM tumor cells. (C) 2017 Elsevier B.V. All rights reserved.
ISSN: 0304-3835
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