Ruxolitinib Regulates the Autophagy Machinery in Multiple Myeloma Cells

Author(s):

Alican Kusoglu*, Bakiye G. Bagca, Neslihan P.O. Ay, Guray Saydam and Cigir B. Avci   Pages 2316 - 2323 ( 8 )

Abstract:

<P>Background: Ruxolitinib is a selective JAK1/2 inhibitor approved by the FDA for myelofibrosis in 2014 and nowadays, comprehensive investigations on the potential of the agent as a targeted therapy for haematological malignancies are on the rise. In multiple myeloma which is a cancer of plasma cells, the Interleukin- 6/JAK/STAT pathway is emerging as a therapeutic target since the overactivation of the pathway is associated with poor prognosis. </P><P> Objective: In this study, our purpose was to discover the potential anticancer effects of ruxolitinib in ARH-77 multiple myeloma cell line compared to NCI-BL 2171 human healthy B lymphocyte cell line. </P><P> Methods: Cytotoxic effects of ruxolitinib in ARH-77 and NCI-BL 2171 cells were determined via WST-1 assay. The autophagy mechanism induced by ruxolitinib measured by detecting autophagosome formation was investigated. Apoptotic effects of ruxolitinib were analyzed with Annexin V-FITC Detection Kit and flow cytometry. We performed RT-qPCR to demonstrate the expression changes of the genes in the IL-6/JAK/STAT pathway in ARH-77 and NCI-BL 2171 cells treated with ruxolitinib. </P><P> Results: We identified the IC50 values of ruxolitinib for ARH-77 and NCI-BL 2171 as 20.03 and 33.9μM at the 72nd hour, respectively. We showed that ruxolitinib induced autophagosome accumulation by 3.45 and 1.70 folds in ARH-77 and NCI-BL 2171 cells compared to the control group, respectively. Treatment with ruxolitinib decreased the expressions of IL-6, IL-18, JAK2, TYK2, and AKT genes, which play significant roles in MM pathogenesis. </P><P> Conclusion: All in all, ruxolitinib is a promising agent for the regulation of the IL-6/JAK/STAT pathway and interferes with the autophagy mechanism in MM.</P>

Keywords:

Ruxolitinib, multiple myeloma, autophagy, Interleukin-6, JAK, STAT.

Affiliation:

Department of Medical Biology, Ege University Medical School, Izmir, Department of Medical Biology, Ege University Medical School, Izmir, Department of Medical Biology, Ege University Medical School, Izmir, Department of Hematology, Ege University Medical School, Izmir, Department of Medical Biology, Ege University Medical School, Izmir

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