Anti-myeloma effects of ruxolitinib combined with bortezomib and lenalidomide: A rationale for JAK/STAT pathway inhibition in myeloma patients.
Cancer Lett
; 403: 206-215, 2017 09 10.
Article
em En
| MEDLINE
| ID: mdl-28645562
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 JAK2 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 SubG0 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.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pirazóis
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Talidomida
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Transdução de Sinais
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Protocolos de Quimioterapia Combinada Antineoplásica
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Fatores de Transcrição STAT
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Janus Quinase 1
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Janus Quinase 2
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Bortezomib
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Mieloma Múltiplo
Limite:
Aged80
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article