Montelukast enhances cytocidal effects of carfilzomib in multiple myeloma by inhibiting mTOR pathway
Montelukast enhances cytocidal effects of carfilzomib in multiple myeloma by inhibiting mTOR pathway
复制标题
孟鲁司特通过抑制 mTOR 通路增强卡非佐米对多发性骨髓瘤的杀细胞作用
DOI：
10.1080/15384047.2018.1529112
复制
发表时间：
2018-10
影响因子：
3.6
通讯作者：
Yan Hua
中科院分区：
文献类型：
--
作者：
Tong Jia;Yu Qing;Xu Wenbin;Yu Wenjun;Wu Chao;Wu Yingli;Yan Hua
摘要 孟鲁司特是一种抗哮喘药物，最近显示出其对癌症增殖的抑制作用。本研究的目的是确定孟鲁司特对多发性骨髓瘤（MM）细胞的细胞毒性作用以及孟鲁司特和卡非佐米治疗MM的联合作用。结果显示，孟鲁司特在 MM 细胞系中诱导剂量和时间依赖性细胞毒性，并显着抑制骨髓瘤细胞的集落形成。此外，孟鲁司特增强了卡非佐米在 MM 细胞系中的细胞毒性。这种抗肿瘤作用与通过抑制 mTOR 信号通路而减少的 c-Myc 相关。此外，即使在骨髓基质细胞（BMSC）存在的情况下，孟鲁司特和卡非佐米的组合也能有效诱导骨髓瘤细胞凋亡。更重要的是要注意，联合治疗在卡非佐米耐药细胞系（U266R 和 8226R）中表现出类似的杀细胞作用。此外，在两个 MM 异种移植小鼠模型和 7 例人 CD138+ 骨髓瘤细胞（4 例新诊断病例和 3 例复发病例）中发现了联合效应，对来自 5 名健康供体的外周血单核细胞 (PBMC) 没有细胞毒性。我们的数据表明，孟鲁司特增强了卡非佐米在卡非佐米敏感和卡非佐米耐药的 MM 细胞系中的细胞毒性。这些发现可能有助于治疗策略的制定，并为难治性骨髓瘤的治疗提供有前景的治疗组合方案。
ABSTRACT Montelukast is an anti-asthmatic medication, and has recently showed its inhibitory effects on the proliferation of cancers. The purpose of this study was to identify the cytotoxic effects of montelukast on multiple myeloma (MM) cells and the combination effects of montelukast and carfilzomib in the treatment of MM. Results revealed that montelukast induced a dose- and time-dependent cytotoxicity in MM cells lines and significantly suppressed the colony formation of myeloma cells. Furthermore, montelukast enhanced the cytotoxicity of carfilzomib in MM cell lines. This anti-tumor effect was associated with decreased c-Myc via the inhibition of mTOR signaling pathway. Moreover, the combination of montelukast and carfilzomib induced apoptosis of myeloma cells effectively, even in the presence of bone marrow stromal cells (BMSCs). It is more important to note that the co-treatment exhibited similar cytocidal effects in carfilzomib-resistant cell lines (U266R and 8226R). In addition, the combined effects were noted in two MM xenograft mice models and 7 cases of human CD138+ myeloma cells (4 newly diagnosed cases and 3 relapsed cases) with no cytotoxicity on peripheral blood mononuclear cells (PBMCs) from 5 healthy donors. Our data suggested that montelukast enhanced the cytotoxicity of carfilzomib in both carfilzomib-sensitive and carfilzomib-resistant MM cell lines. These findings may facilitate the development of therapeutic strategies and provide a promising therapeutic combination regimen for the treatment of refractory myeloma.
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影响因子：
2
作者：
R. Dmochowski
通讯作者：
R. Dmochowski
DOI：
10.1016/j.respe.2020.09.004
发表时间：
2020-10-10
期刊：
Revue D'Epidemiologie et De Sante Publique
影响因子：
--
作者：
La rédaction
通讯作者：
La rédaction
影响因子：
9.3
作者：
通讯作者：
--
影响因子：
5.9
作者：
Craighead FL
通讯作者：
Craighead FL