The FAP α -activated prodrug Z-GP-DAVLBH inhibits the growth and pulmonary metastasis of osteosarcoma cells by suppressing the AXL pathway

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

doi:10.1016/j.apsb.2021.08.015

The FAP α -activated prodrug Z-GP-DAVLBH inhibits the growth and pulmonary metastasis of osteosarcoma cells by suppressing the AXL pathway

Acta Pharm Sin B. 2022 Mar;12(3):1288-1304. doi: 10.1016/j.apsb.2021.08.015. Epub 2021 Aug 14.

Authors

Geni Ye^{1

2}, Maohua Huang^{1

2

3}, Yong Li^{1

2}, Jie Ouyang^{1

2}, Minfeng Chen^{1

2}, Qing Wen^{1

2}, Xiaobo Li^{1

2}, Huhu Zeng^{1

2}, Pei Long^{1

2}, Zepei Fan⁴, Junqiang Yin⁴, Wencai Ye^{1

2}, Dongmei Zhang^{1

2}

Affiliations

¹ College of Pharmacy, Jinan University, Guangzhou 510632, China.
² Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, Guangzhou 510632, China.
³ Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou 510632, China.
⁴ Department of Musculoskeletal Oncology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.

Abstract

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.

Keywords: AXL; DAVLBH, desacetylvinblastine monohydrazide; EMT, epithelial–mesenchymal transition; FAPα, fibroblast activation protein alpha; Fibroblast activation protein alpha; Growth; Osteosarcoma; Pulmonary metastasis; TA-MSCs, tumor-associated mesenchymal stem cells; Vinblastine prodrug; Z-GP, N-terminal benzyloxy carbonyl-blocked (Z-blocked) GlyPro peptide; Z-GP-DAVLBH, desacetylvinblastine monohydrazide coupled to an N-terminal benzyloxy carbonyl-blocked (Z-blocked) GlyPro peptide; siRNA, small interfering RNA; β-Catenin.