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
College of Pharmacy, Jinan University, Guangzhou 510632, China.
Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, Guangzhou 510632, China.
Acta Pharm Sin B. 2022 Mar;12(3):1288-1304. doi: 10.1016/j.apsb.2021.08.015. Epub 2021 Aug 14.
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 (FAP) is upregulated in osteosarcoma and critically associated with osteosarcoma progression and metastasis, demonstrating that FAP-targeted agents might be a promising therapeutic strategy for osteosarcoma. In the present study, we reported that the FAP-activated vinblastine prodrug Z-GP-DAVLBH exhibited potent antitumor activities against FAP-positive osteosarcoma cells and . 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 and suppressed pulmonary metastasis of osteosarcoma xenografts . Mechanistically, Z-GP-DAVLBH suppressed the AXL/AKT/GSK-3/-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 FAP-positive osteosarcoma, particularly osteosarcoma with pulmonary metastases.
骨肉瘤是一种具有高度增殖和侵袭特性、肺转移发生率高且预后较差的骨肿瘤。化疗是骨肉瘤治疗的主要手段。目前，尚无获批用于骨肉瘤治疗的分子靶向药物，尤其是针对伴有肺转移的骨肉瘤的有效药物。据报道，成纤维细胞活化蛋白α（FAP）在骨肉瘤中上调，且与骨肉瘤的进展和转移密切相关，这表明靶向FAP的药物可能是一种有前景的骨肉瘤治疗策略。在本研究中，我们报道了FAP激活的长春碱前药Z-GP-DAVLBH对FAP阳性骨肉瘤细胞具有强大的抗肿瘤活性。Z-GP-DAVLBH抑制骨肉瘤细胞的生长并诱导其凋亡。重要的是，它还降低了骨肉瘤细胞的迁移和侵袭能力，逆转了骨肉瘤细胞的上皮-间质转化（EMT），并抑制了骨肉瘤异种移植瘤的肺转移。机制上，Z-GP-DAVLBH抑制AXL/AKT/GSK-3/β-连环蛋白通路，从而抑制骨肉瘤细胞的生长和转移扩散。这些发现表明，Z-GP-DAVLBH是一种有前景的治疗FAP阳性骨肉瘤，尤其是伴有肺转移的骨肉瘤的药物。
