Department of Medical Biology, Ege University Medical School, Izmir, Turkey.
Department of Hematology, Ege University Medical School, Izmir, Turkey.
Anticancer Agents Med Chem. 2020;20(18):2316-2323. doi: 10.2174/1871520620666200218105159.
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.
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.
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.
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.
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.
鲁索利替尼是一种选择性 JAK1/2 抑制剂，于 2014 年被美国食品药品监督管理局批准用于骨髓纤维化，如今，针对该药物作为血液恶性肿瘤靶向治疗的潜力的综合研究正在兴起。在多发性骨髓瘤中，白细胞介素-6/JAK/STAT 途径作为一种治疗靶点正在出现，因为该途径的过度激活与预后不良有关。
在这项研究中，我们的目的是与 NCI-BL 2171 人健康 B 淋巴细胞系相比，发现鲁索利替尼在 ARH-77 多发性骨髓瘤细胞系中的潜在抗癌作用。
通过 WST-1 测定法确定鲁索利替尼对 ARH-77 和 NCI-BL 2171 细胞的细胞毒性作用。通过检测自噬体形成来研究鲁索利替尼诱导的自噬机制。用 Annexin V-FITC 检测试剂盒和流式细胞术分析鲁索利替尼的凋亡作用。我们进行 RT-qPCR 以证明 ARH-77 和 NCI-BL 2171 细胞中 IL-6/JAK/STAT 通路基因的表达变化。
我们确定了鲁索利替尼对 ARH-77 和 NCI-BL 2171 的 IC50 值分别为 72 小时时的 20.03 和 33.9μM。我们表明，与对照组相比，鲁索利替尼分别使 ARH-77 和 NCI-BL 2171 细胞中的自噬体积累增加了 3.45 和 1.70 倍。鲁索利替尼治疗降低了 IL-6、IL-18、JAK2、TYK2 和 AKT 基因的表达，这些基因在 MM 的发病机制中起着重要作用。
总之，鲁索利替尼是一种有前途的调节 IL-6/JAK/STAT 通路的药物，并干扰 MM 中的自噬机制。
