Blom Kristin, Senkowski Wojciech, Jarvius Malin, Berglund Malin, Rubin Jenny, Lenhammar Lena, Parrow Vendela, Andersson Claes, Loskog Angelica, Fryknäs Mårten, Nygren Peter, Larsson Rolf
a Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine , Uppsala University , Uppsala , Sweden.
b Department of Immunology, Genetics and Pathology, Science for Life Laboratory , Uppsala University , Uppsala , Sweden.
Immunopharmacol Immunotoxicol. 2017 Aug;39(4):199-210. doi: 10.1080/08923973.2017.1320671. Epub 2017 May 4.
Mebendazole (MBZ), a drug commonly used for helminitic infections, has recently gained substantial attention as a repositioning candidate for cancer treatment. However, the mechanism of action behind its anticancer activity remains unclear. To address this problem, we took advantage of the curated MBZ-induced gene expression signatures in the LINCS Connectivity Map (CMap) database. The analysis revealed strong negative correlation with MEK/ERK1/2 inhibitors. Moreover, several of the most upregulated genes in response to MBZ exposure were related to monocyte/macrophage activation. The MBZ-induced gene expression signature in the promyeloblastic HL-60 cell line was strongly enriched in genes involved in monocyte/macrophage pro-inflammatory (M1) activation. This was subsequently validated using MBZ-treated THP-1 monocytoid cells that demonstrated gene expression, surface markers and cytokine release characteristic of the M1 phenotype. At high concentrations MBZ substantially induced the release of IL-1β and this was further potentiated by lipopolysaccharide (LPS). At low MBZ concentrations, cotreatment with LPS was required for MBZ-stimulated IL-1β secretion to occur. Furthermore, we show that the activation of protein kinase C, ERK1/2 and NF-kappaB were required for MBZ-induced IL-1β release. MBZ-induced IL-1β release was found to be dependent on NLRP3 inflammasome activation and to involve TLR8 stimulation. Finally, MBZ induced tumor-suppressive effects in a coculture model with differentiated THP-1 macrophages and HT29 colon cancer cells. In summary, we report that MBZ induced a pro-inflammatory (M1) phenotype of monocytoid cells, which may, at least partly, explain MBZ's anticancer activity observed in animal tumor models and in the clinic.
甲苯咪唑（MBZ）是一种常用于治疗蠕虫感染的药物，最近作为一种癌症治疗的重新定位候选药物受到了广泛关注。然而，其抗癌活性背后的作用机制仍不清楚。为了解决这个问题，我们利用了LINCS连接图谱（CMap）数据库中精心策划的MBZ诱导的基因表达特征。分析显示与MEK/ERK1/2抑制剂呈强烈负相关。此外，一些对MBZ暴露反应上调最明显的基因与单核细胞/巨噬细胞活化有关。早幼粒细胞HL-60细胞系中MBZ诱导的基因表达特征在参与单核细胞/巨噬细胞促炎（M1）活化的基因中高度富集。随后，使用经MBZ处理的THP-1单核细胞样细胞进行了验证，这些细胞表现出M1表型的基因表达、表面标志物和细胞因子释放特征。在高浓度下，MBZ可显著诱导IL-1β的释放，脂多糖（LPS）可进一步增强这种作用。在低MBZ浓度下，需要与LPS共同处理才能发生MBZ刺激的IL-1β分泌。此外，我们发现蛋白激酶C、ERK1/2和NF-κB的激活是MBZ诱导IL-1β释放所必需的。发现MBZ诱导的IL-1β释放依赖于NLRP3炎性小体的激活，并涉及TLR8刺激。最后，在与分化的THP-1巨噬细胞和HT29结肠癌细胞的共培养模型中，MBZ诱导了肿瘤抑制作用。总之，我们报告MBZ诱导了单核细胞样细胞促炎（M1）表型，这可能至少部分解释了在动物肿瘤模型和临床中观察到的MBZ的抗癌活性。
