Ruxolitinib Regulates the Autophagy Machinery in Multiple Myeloma Cells

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Author(s): Alican Kusoglu*, Bakiye G. Bagca*, Neslihan P. Ozates Ay, Guray Saydam, Cigir B. Avci.

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

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Background: Ruxolitinib is a selective JAK1/2 inhibitor approved by 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, Interleukin-6/JAK/STAT pathway is emerging as a therapeutic target since the over activation of the pathway is associated with poor prognosis.

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.

Methods: Cytotoxic effects of ruxolitinib in ARH-77 and NCI-BL 2171 cells were determined via WST-1 assay. Investigation of the autophagy mechanism induced by ruxolitinib measured by detecting autophagosome formation. 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 IL-6/JAK/STAT pathway in ARH-77 and NCI-BL 2171 cells treated with ruxolitinib.

Results: We identified the IC50 values of ruxolitinib for ARH-77 and NCI-BL 2171 as 20.03 and 33.9μM at the 72th 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 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.

Conclusion: All in all, ruxolitinib is a promising agent for the regulation of IL-6/JAK/STAT pathway and interfering with autophagy mechanism in MM.

Keywords: Ruxolitinib, Multiple myeloma, Autophagy, Interleukin-6, JAK, STAT

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(E-pub Ahead of Print)
DOI: 10.2174/1871520620666200218105159
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