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.

骨肉瘤是一类具有高度增殖性和侵袭性、肺转移发生率高、预后差的骨肿瘤。化疗是骨肉瘤的主要治疗方法。目前，尚无批准用于骨肉瘤治疗的分子靶向药物，尤其是对骨肉瘤肺转移有效的药物。据报道，成纤维细胞活化蛋白 α (FAP α ) 在骨肉瘤中上调，并且与骨肉瘤的进展和转移密切相关，表明 FAP α靶向药物可能是一种有前途的骨肉瘤治疗策略。在本研究中，我们报道了 FAP α-激活的长春碱前药 Z-GP-DAVLBH在体外和体内对 FAP α阳性骨肉瘤细胞表现出有效的抗肿瘤活性。Z-GP-DAVLBH抑制骨肉瘤细胞的生长并诱导其凋亡。重要的是，它还在体外降低了骨肉瘤细胞的迁移和侵袭能力并逆转了上皮-间质转化 (EMT)，并在体内抑制了骨肉瘤异种移植物的肺转移。从机制上讲，Z-GP-DAVLBH 抑制 AXL/AKT/GSK-3 β / β-catenin 通路，导致抑制骨肉瘤细胞的生长和转移扩散。这些发现表明 Z-GP-DAVLBH 是一种很有前途的药物，可用于治疗 FAP α阳性骨肉瘤，尤其是伴有肺转移的骨肉瘤。