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二乙基二硫代氨基甲酸盐铜(I)通过抑制MET/PI3K/AKT信号通路来抑制人骨肉瘤细胞的生长。

DDTC-Cu(I) inhibits human osteosarcoma cells growth by repressing MET/PI3K/AKT signaling pathway.

作者信息

Zhou Ruhao, Yan Lei, Zhang Kun, Chen Song, Yu Yang, Wei Xiaochun, Pan Yongchun, Xu Chaojian, Sun Xiaojuan, Lv Zhi, Li Pengcui, Qiao Xiaochen, Feng Yi, Tian Zhi

机构信息

Second Clinical Medical College, Shanxi Medical University, 382 Wuyi Road, Taiyuan, 030001, Shanxi, People's Republic of China.

Department of Orthopedics, Shanxi Key laboratory of Bone and Soft Tissue Injury Repair, The Second Hospital of Shanxi Medical University, 382 Wuyi Road, Taiyuan, 030001, Shanxi, People's Republic of China.

出版信息

Sci Rep. 2025 Jul 1;15(1):21780. doi: 10.1038/s41598-025-06748-6.


DOI:10.1038/s41598-025-06748-6
PMID:40594499
Abstract

Osteosarcoma (OS) is a frequently occurring bone malignancy with increased metastatic properties, causing deaths in large numbers around the world. Disulfiram (DSF) is clinically utilized to treat alcohol dependency and has been indicated to bind Cu(I) in-vivo to form DDTC-Cu(I), which has been confirmed for its antitumor effects. This investigation aimed to elucidate the efficacy of DDTC-Cu(I) on OS cell apoptosis, migration, growth, invasion, and underlying mechanisms. The in-vitro investigations were performed on U2OS, SaOS2, and MG-63 OS cell lines and included CCK-8, colony formation, RTCA, transwell invasion, flow cytometry, wound healing, and RNA seq assays. DDTC-Cu(I) was inoculated dose-dependent, increased apoptosis, and suppressed cells' ability to proliferate, migrate, and invade via the MET and PI3K/AKT signaling pathways. Additionally, MET's overexpression partially reversed the anti-OS and PI3K/AKT signaling pathways suppression effect of DDTC-Cu(I). Furthermore, the SaOS2 xenograft mice model was utilized to confirm the in-vivo anti-OS efficacy of DDTC-Cu(I) by MET protein inhibition. The histological research revealed that DDTC-Cu(I) had no adverse influence on the liver, heart, lungs, and kidneys. Overall, the data of this investigation suggested that DDTC-Cu(I) could serve as an efficient agent against OS development.

摘要

骨肉瘤(OS)是一种常见的具有高转移特性的骨恶性肿瘤,在全球导致大量死亡。双硫仑(DSF)在临床上用于治疗酒精依赖,并且已表明其在体内与Cu(I)结合形成二乙胺基二硫代甲酸盐-Cu(I)(DDTC-Cu(I)),其抗肿瘤作用已得到证实。本研究旨在阐明DDTC-Cu(I)对OS细胞凋亡、迁移、生长、侵袭的影响及其潜在机制。体外实验在U2OS、SaOS2和MG-63骨肉瘤细胞系上进行,包括CCK-8、集落形成、实时细胞分析、Transwell侵袭、流式细胞术、伤口愈合和RNA测序分析。DDTC-Cu(I)呈剂量依赖性接种,增加细胞凋亡,并通过MET和PI3K/AKT信号通路抑制细胞增殖、迁移和侵袭能力。此外,MET的过表达部分逆转了DDTC-Cu(I)对骨肉瘤及PI3K/AKT信号通路的抑制作用。此外,利用SaOS2异种移植小鼠模型通过抑制MET蛋白来证实DDTC-Cu(I)在体内的抗骨肉瘤疗效。组织学研究表明,DDTC-Cu(I)对肝脏、心脏、肺和肾脏没有不良影响。总体而言,本研究数据表明,DDTC-Cu(I)可作为一种有效的抗骨肉瘤药物。

相似文献

[1]
DDTC-Cu(I) inhibits human osteosarcoma cells growth by repressing MET/PI3K/AKT signaling pathway.

Sci Rep. 2025-7-1

[2]
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[3]
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[4]
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[5]
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[6]
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[7]
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[8]
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[9]
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[10]
Polydatin sensitizes osteosarcoma cells to methotrexate through suppressing the H19/H3K27me3/H3K9me3 mediated folate metabolism regulatory axis.

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本文引用的文献

[1]
KEGG: biological systems database as a model of the real world.

Nucleic Acids Res. 2025-1-6

[2]
Functional role of MicroRNA/PI3K/AKT axis in osteosarcoma.

Front Oncol. 2023-6-19

[3]
Gene Expression and Cellular Copper Levels between Low and Highly Metastatic Osteosarcoma Provide a Case for Novel Repurposing with Disulfiram and Copper.

Sarcoma. 2022-1-28

[4]
Roles of MET in human cancer.

Clin Chim Acta. 2022-1-15

[5]
Effect of the Notch1-mediated PI3K-Akt-mTOR pathway in human osteosarcoma.

Aging (Albany NY). 2021-9-8

[6]
Circular RNA circ_001422 promotes the progression and metastasis of osteosarcoma via the miR-195-5p/FGF2/PI3K/Akt axis.

J Exp Clin Cancer Res. 2021-7-16

[7]
miR-135a Reduces Osteosarcoma Pulmonary Metastasis by Targeting Both BMI1 and KLF4.

Front Oncol. 2021-3-22

[8]
The disulfiram/copper complex induces apoptosis and inhibits tumour growth in human osteosarcoma by activating the ROS/JNK signalling pathway.

J Biochem. 2021-10-11

[9]
MACC1 Contributes to the Development of Osteosarcoma Through Regulation of the HGF/c-Met Pathway and Microtubule Stability.

Front Cell Dev Biol. 2020-12-23

[10]
miR-485-3p regulated by MALAT1 inhibits osteosarcoma glycolysis and metastasis by directly suppressing c-MET and AKT3/mTOR signalling.

Life Sci. 2021-3-1

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