Anti-Myeloma effects of ruxolitinib combined with bortezomib and lenalidomide: A rationale for jak/stat pathway inhibition in myeloma patients

• Published in: Cancer letters 2017-09, Vol.403, p.206-215
• Main Authors: de Oliveira, Mariana B, Fook-Alves, Veruska L, Eugenio, Angela I.P, Fernando, Rodrigo C, Sanson, Luiz Felipe G, de Carvalho, Mariana F, Braga, Walter M.T, Davies, Faith E, Colleoni, Gisele W.B
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Autophagy; Bone marrow; Bortezomib; Bortezomib - pharmacology; Cancer therapies; Cell culture; Cell cycle; Cell Cycle - drug effects; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell death; Cell Line, Tumor; Cell proliferation; Coculture Techniques; Dexamethasone; Dose-Response Relationship, Drug; Drug therapy; Female; Flow cytometry; Gene expression; Gene Expression Regulation, Neoplastic; Hematology, Oncology and Palliative Medicine; Humans; Immunotherapy; Inhibition; Inhibitor drugs; JAK/STAT; JAK1; JAK2; Janus Kinase 1 - antagonists & inhibitors; Janus Kinase 1 - genetics; Janus Kinase 1 - metabolism; Janus Kinase 2 - antagonists & inhibitors; Janus Kinase 2 - genetics; Janus Kinase 2 - metabolism; Kinases; Male; Middle Aged; Multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - enzymology; Multiple Myeloma - genetics; Multiple Myeloma - pathology; Penicillin; Proteins; Pyrazoles - pharmacology; Real time; Ruxolitinib; Signal Transduction - drug effects; Small molecule inhibitor; STAT Transcription Factors - metabolism; Stromal cells; Stromal Cells - drug effects; Stromal Cells - metabolism; Stromal Cells - pathology; Substance abuse treatment; Survival; Targeted cancer therapy; Thalidomide - analogs & derivatives; Thalidomide - pharmacology; Time Factors; Tumor cells; Tumors
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2017.06.016

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, and. 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.