Original articles
Geni Ye, Maohua Huang, Yong Li, Jie Ouyang, Minfeng Chen, Qing Wen, Xiaobo Li, Huhu Zeng, Pei Long, Zepei Fan, Junqiang Yin, Wencai Ye, Dongmei Zhang. The FAPα-activated prodrug Z-GP-DAVLBH inhibits the growth and pulmonary metastasis of osteosarcoma cells by suppressing the AXL pathway[J]. Acta Pharmaceutica Sinica B, 2022, 12(3): 1288-1304

The FAPα-activated prodrug Z-GP-DAVLBH inhibits the growth and pulmonary metastasis of osteosarcoma cells by suppressing the AXL pathway
Geni Yea,b, Maohua Huanga,b,c, Yong Lia,b, Jie Ouyanga,b, Minfeng Chena,b, Qing Wena,b, Xiaobo Lia,b, Huhu Zenga,b, Pei Longa,b, Zepei Fand, Junqiang Yind, Wencai Yea,b, Dongmei Zhanga,b
a. College of Pharmacy, Jinan University, Guangzhou 510632, China;
b. Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, Guangzhou 510632, China;
c. Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou 510632, China;
d. Department of Musculoskeletal Oncology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
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.
Key words:    Osteosarcoma    Fibroblast activation protein alpha    Growth    Pulmonary metastasis    Vinblastine prodrug    AXL    β-Catenin   
Received: 2021-06-04     Revised: 2021-07-27
DOI: 10.1016/j.apsb.2021.08.015
Funds: This work was supported by National Natural Science Foundation of China (grant numbers:82003796, 81803566, 81973340 and 81630095); Local Innovative and Research Teams Project of the Guangdong Pearl River Talents Program (grant number:2017BT01Y036, China); National High-level Personnel of the Special Support Program (DM Zhang, China); National Science and Technology Major Project (grant number:2018ZX09711001-008-008, China); Key-Area Research and Development Program of Guangdong Province (grant number:2020B1111110004, China); Natural Science Foundation of Guangdong Province (grant number:2019A1515010144, China); Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy (grant number:2020B1212060076, China); Special Funds for the Cultivation of Guangdong College Students' Scientific and Technological Innovation (grant number:pdjh2021a0052, China).
Corresponding author: Junqiang Yin,E-mai:yinjunq@mail.sysu.edu.cn;Wencai Ye,E-mai:chywc@aliyun.com;Dongmei Zhang,E-mai:dmzhang701@jnu.edu.cn     Email:yinjunq@mail.sysu.edu.cn;chywc@aliyun.com;dmzhang701@jnu.edu.cn
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Geni Ye
Maohua Huang
Yong Li
Jie Ouyang
Minfeng Chen
Qing Wen
Xiaobo Li
Huhu Zeng
Pei Long
Zepei Fan
Junqiang Yin
Wencai Ye
Dongmei Zhang

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