Utidelone inhibits growth of colorectal cancer cells through ROS/JNK signaling pathway.
Utidelone inhibits growth of colorectal cancer cells through ROS/JNK signaling pathway.
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乌替隆通过ROS/JNK信号通路抑制结直肠癌细胞生长
DOI：
10.1038/s41419-021-03619-6
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发表时间：
2021-04-01
影响因子：
9
通讯作者：
Tu S
中科院分区：
文献类型：
--
作者：
Li F;Huang T;Tang Y;Li Q;Wang J;Cheng X;Zhang W;Zhang B;Zhou C;Tu S
Utidelone (UTD1)是一种新型微管稳定剂，是通过基因工程生产的埃坡霉素B类似物。 UTD1 在多种实体瘤中表现出广泛的抗肿瘤活性。然而，其在结直肠癌（CRC）中的活性和机制仍有待研究。在这项研究中，UTD1 在体外显着抑制 CRC 细胞增殖（RKO 和 HCT116 中的 IC50 分别为 0.38μg/ml、0.77μg/ml）。免疫荧光染色显示UTD1诱导RKO细胞中微管束和紫苑的形成。流式细胞术分析表明，UTD1 诱导细胞周期停滞在 G2/M 期，随后发生细胞凋亡。值得注意的是，UTD1比紫杉醇和5-FU表现出更强的诱导凋亡作用，尤其是在ABCB1高表达的HCT15细胞中。 UTD1暴露会裂解caspase-3和聚ADP核糖聚合酶（PARP），降低线粒体膜电位，释放细胞色素c，增加活性氧的产生并激活c-Jun N末端激酶（JNK），表明ROS/JNK途径参与了这一过程。此外，UTD1在裸鼠RKO异种移植瘤中抑制肿瘤生长，比紫杉醇和5-FU更有效、更安全。总而言之，我们的研究结果首先表明 UDT1 抑制 CRC 异种移植模型中的肿瘤生长，并且可能是 CRC 治疗的有前途的药物。
Utidelone (UTD1), a novel microtubule stabilizing agent, is an epothilone B analogue which was produced by genetic engineering. UTD1 has exhibited broad antitumor activity in multiple solid tumors. However, its activity and mechanism in colorectal cancer (CRC) remain to be studied. In this study, UTD1 dramatically inhibited CRC cell proliferation (with 0.38 µg/ml, 0.77 µg/ml IC50 in RKO and HCT116, respectively) in vitro. Immunofluorescence staining showed that UTD1 induced the formation of microtubule bundling and asters in RKO cells. Flow cytometry analysis demonstrated that UTD1 induced cell cycle to arrest in G2/M phase, subsequent apoptosis. Significantly, UTD1 exhibited stronger effect on inducing apoptosis than paclitaxel and 5-FU, especially in HCT15 cells which is ABCB1 high-expression. UTD1 exposure cleaved caspase-3 and poly ADP-ribose polymerase (PARP), decreased mitochondrial membrane potential, released cytochrome c, increased the production of active oxygen and activated c-Jun N-terminal kinase (JNK), suggesting ROS/JNK pathway was involved in this process. Moreover, UTD1 inhibited tumor growth and was more effective and safer compared with paclitaxel and 5-FU in RKO xenograft in nude mice. Taken together, our findings first indicate that UDT1 inhibits tumor growth in CRC xenograft model and may be a promising agent for CRC treatment.
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影响因子：
37.3
作者：
Risinger AL;Riffle SM;Lopus M;Jordan MA;Wilson L;Mooberry SL
通讯作者：
Mooberry SL
DOI：
10.1158/1078-0432.ccr-15-2184
发表时间：
2016-07-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Montero AJ;Kwon D;Flores A;Kovacs K;Trent JC;Benedetto P;Rocha-Lima C;Merchan JR
通讯作者：
Merchan JR
影响因子：
37.3
作者：
Chen, Xiaoxiang;Xu, Mu;Wang, Shukui
通讯作者：
Wang, Shukui
影响因子：
5.8
作者：
Pellicciotta I;Yang CP;Venditti CA;Goldberg GL;Shahabi S
通讯作者：
Shahabi S
影响因子：
12.4
作者：
Li, R;Moudgil, T;Hu, HM
通讯作者：
Hu, HM