Tocilizumab (monoclonal anti-IL-6R antibody) reverses anlotinib resistance in osteosarcoma.
Tocilizumab (monoclonal anti-IL-6R antibody) reverses anlotinib resistance in osteosarcoma.
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DOI：
10.3389/fonc.2023.1192472
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发表时间：
2023
影响因子：
4.7
通讯作者：
Tang, Xiaodong
中科院分区：
文献类型：
--
作者：
Xu, Jiuhui;Chen, Chenglong;Sun, Kunkun;Shi, Qianyu;Wang, Boyang;Huang, Yi;Ren, Tingting;Tang, Xiaodong
Anlotinib是一种酪氨酸激酶抑制剂（TKI），已在临床应用于抑制骨肉瘤（OS）的恶性细胞生长和肺转移。但在治疗过程中出现了多种耐药现象。我们的目标是探索新的靶点来逆转OS中的anlotinib耐药。在本研究中，我们建立了4个OS anlotinib耐药细胞系，并进行了rna测序来评估差异表达基因。采用PCR、western blot和ELISA法对rna序列进行验证。我们通过CCK8、EDU、菌落形成、凋亡、transwell、伤口愈合、Cytoskeletal染色试验和异种移植裸鼠模型进一步探讨了tocilizumab（抗IL-6受体）单独使用或与anlotinib联合使用对anlotinib耐药OS细胞恶性活力的抑制作用。采用免疫组化法检测104例骨肉瘤组织中IL-6的表达。我们发现IL-6及其下游通路STAT3在耐安洛替尼骨肉瘤中被激活。Tocilizumab损害了anlotinib耐药OS细胞的肿瘤进展，并且与anlotinib联合治疗通过抑制STAT3表达增强了这些作用。IL-6在OS患者中高表达，且与预后不良相关。Tocilizumab可通过IL-6/STAT3途径逆转OS的anlotinib耐药，与anlotinib联合治疗使OS的进一步研究和临床治疗合理化。
Anlotinib, a tyrosine kinase inhibitor (TKI) has been in clinical application to inhibit malignant cell growth and lung metastasis in osteosarcoma (OS). However, a variety of drug resistance phenomena have been observed in the treatment. We aim to explore the new target to reverse anlotinib resistance in OS. In this study, we established four OS anlotinib-resistant cell lines, and RNA-sequence was performed to evaluate differentially expressed genes. We verified the results of RNA-sequence by PCR, western blot and ELISA assay. We further explored the effects of tocilizumab (anti- IL-6 receptor), either alone or in combined with anlotinib, on the inhibition of anlotinib-resistant OS cells malignant viability by CCK8, EDU, colony formation, apoptosis, transwell, wound healing, Cytoskeletal stain assays, and xenograft nude mouse model. The expression of IL-6 in 104 osteosarcoma samples was tested by IHC. We found IL-6 and its downstream pathway STAT3 were activated in anlotinib-resistant osteosarcoma. Tocilizumab impaired the tumor progression of anlotinib-resistant OS cells, and combined treatment with anlotinib augmented these effects by inhibiting STAT3 expressions. IL-6 was highly expressed in patients with OS and correlated with poor prognosis. Tocilizumab could reverse anlotinib resistance in OS by IL-6/STAT3 pathway and the combination treatment with anlotinib rationalized further studies and clinical treatment of OS.
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DOI：
10.1007/s00262-021-02876-w
发表时间：
2021-09
期刊：
Cancer immunology, immunotherapy : CII
影响因子：
--
作者：
Boye K;Longhi A;Guren T;Lorenz S;Næss S;Pierini M;Taksdal I;Lobmaier I;Cesari M;Paioli A;Løndalen AM;Setola E;Hompland I;Meza-Zepeda LA;Sundby Hall K;Palmerini E
通讯作者：
Palmerini E
影响因子：
8.5
作者：
Liu Y;Liao S;Bennett S;Tang H;Song D;Wood D;Zhan X;Xu J
通讯作者：
Xu J
影响因子：
50.5
作者：
Grignani, G.;Palmerini, E.;Aglietta, M.
通讯作者：
Aglietta, M.
二甲双胍通过抑制 IL-6 信号传导和 EMT 逆转，在体外和体内使 EGFR-TKI 耐药的人肺癌细胞变得敏感
影响因子：
11.5
作者：
Li, Li;Han, Rui;He, Yong
通讯作者：
He, Yong
影响因子：
4
作者：
Liu Z;Gao S;Zhu L;Wang J;Zhang P;Li P;Zhang F;Yao W
通讯作者：
Yao W