The FAP α -activated prodrug Z-GP-DAVLBH inhibits the growth and pulmonary metastasis of osteosarcoma cells by suppressing the AXL pathway.
The FAP α -activated prodrug Z-GP-DAVLBH inhibits the growth and pulmonary metastasis of osteosarcoma cells by suppressing the AXL pathway.
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FAPα 激活的前药 Z-GP-DAVLBH 通过抑制 AXL 途径抑制骨肉瘤细胞的生长和肺转移
DOI：
10.1016/j.apsb.2021.08.015
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发表时间：
2022-03
影响因子：
14.5
通讯作者：
Zhang, Dongmei
中科院分区：
文献类型：
--
作者：
Ye, Geni;Huang, Maohua;Li, Yong;Ouyang, Jie;Chen, Minfeng;Wen, Qing;Li, Xiaobo;Zeng, Huhu;Long, Pei;Fan, Zepei;Yin, Junqiang;Ye, Wencai;Zhang, Dongmei
关键词：
骨肉瘤是一种具有高度增殖性和侵袭性的骨肿瘤，肺转移发生率高，预后差。化疗是骨肉瘤的主要治疗手段。目前，还没有分子靶向药物被批准用于骨肉瘤的治疗，特别是对骨肉瘤肺转移有效的药物。成纤维细胞活化蛋白α（fibroblast activation protein alpha，FAPα）在骨肉瘤中表达上调，与骨肉瘤的进展和转移密切相关，提示以FAPα为靶点的药物有望成为骨肉瘤的治疗策略。本文报道了FAPα激活的长春碱前体药物Z-GP-DAVLBH对FAPα阳性骨肉瘤细胞的体内外抗肿瘤活性。Z-GP-DAVLBH能抑制骨肉瘤细胞的生长并诱导其凋亡。更重要的是，它还在体外降低骨肉瘤细胞的迁移和侵袭能力，逆转上皮间质转化（EMT），并在体内抑制骨肉瘤异种移植物的肺转移。在机制上，Z-GP-DAVLBH抑制AXL/AKT/GSK-3β/β-catenin途径，导致抑制骨肉瘤细胞的生长和转移扩散。这些结果表明，Z-GP-DAVLBH是一种有前途的药物，用于治疗FAPα阳性骨肉瘤，特别是肺转移的骨肉瘤。FAPα激活的长春碱前药Z-GP-DAVLBH可抑制AXL/AKT/GSK-3β/β-catenin通路的激活，从而抑制FAPα阳性骨肉瘤细胞的生长、上皮-间质转化和肺转移。
Osteosarcoma is a kind of bone tumor with highly proliferative and invasive properties, a high incidence of pulmonary metastasis and a poor prognosis. Chemotherapy is the mainstay of treatment for osteosarcoma. Currently, there are no molecular targeted drugs approved for osteosarcoma treatment, particularly effective drugs for osteosarcoma with pulmonary metastases. It has been reported that fibroblast activation protein alpha (FAPα) is upregulated in osteosarcoma and critically associated with osteosarcoma progression and metastasis, demonstrating that FAPα-targeted agents might be a promising therapeutic strategy for osteosarcoma. In the present study, we reported that the FAPα-activated vinblastine prodrug Z-GP-DAVLBH exhibited potent antitumor activities against FAPα-positive osteosarcoma cells in vitro and in vivo. Z-GP-DAVLBH inhibited the growth and induced the apoptosis of osteosarcoma cells. Importantly, it also decreased the migration and invasion capacities and reversed epithelial–mesenchymal transition (EMT) of osteosarcoma cells in vitro and suppressed pulmonary metastasis of osteosarcoma xenografts in vivo. Mechanistically, Z-GP-DAVLBH suppressed the AXL/AKT/GSK-3β/β-catenin pathway, leading to inhibition of the growth and metastatic spread of osteosarcoma cells. These findings demonstrate that Z-GP-DAVLBH is a promising agent for the treatment of FAPα-positive osteosarcoma, particularly osteosarcoma with pulmonary metastases. The FAPα-activated vinblastine prodrug Z-GP-DAVLBH inhibited the activation of the AXL/AKT/GSK-3β/β-catenin pathway and consequently suppressed the growth, epithelial–mesenchymal transition, and pulmonary metastasis of FAPα-positive osteosarcoma cells.
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