Cyy260 suppresses the proliferation, migration and tumor growth of osteosarcoma by targeting PDGFR-β signaling pathway. (1st November 2022)

• Record Type: Journal Article
• Authors: Qiu, Yinda; Yan, Hao; Zheng, Ruiling; Chen, Xiaojing; Wang, Yi; Yan, Qi; Ye, Yanfei; Zhang, Jianxia; Han, Haoyi; Wang, Kun; Zhao, Yunjie; Huang, Lehao; Li, Xiaokun; Liu, Zhiguo
• Is Part Of: Chemico-biological interactions. Volume 367(2022)
• Publication Date: 2022-11-01
• Subjects: Osteosarcoma -- PDGFR-β -- cyy260 -- Inhibitor -- Antitumor; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2022.110200
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: Osteosarcoma (OS) is a group of malignant tumors with high rates of malignancy and metastasis. OS most commonly affects adolescents and young individuals. However, owing to the lack of effective targeted treatments, the 5-year survival rate for OS is still around 20%. Thus, it is essential to develop effective drugs with low toxicity for OS treatment. In the present study, we investigated the antitumor effect and underlying mechanism of cyy260 in OS via suppressing PDGFR-β and its downstream pathway. We demonstrated that cyy260 inhibits OS cell proliferation and promotes apoptosis via inducing DNA damage and causing cell cycle arrest. More importantly, cyy260 also significantly inhibits tumor migration. Further analysis of molecular mechanisms confirmed that PDGFR-β and its downstream AKT, STAT3, and ERK were involved in the cyy260-mediated antitumor effect. Analysis of subcutaneously transplanted tumors in mice showed that cyy260 suppressed tumor cell growth and exhibited low toxicity in vivo . Collectively, these findings proved that cyy260 could serve as a promising PDGFR-β inhibitor for the treatment of OS. Graphical abstract: cyy260 as a PDGFR-β inhibitor could inhibit the proliferation of MG63 and MNNG cells by suppressing the phosphorylation of PDGFR-β and its downstream ERK, AKT and STAT3. Additionally, cyy260 also exhibited significant in vivo antitumor potency in osteosarcoma cancer cell MNNG/HOS-derived xenograft models. Image 1 Highlights: cyy260 is a small molecule inhibitor with the ability to inhibit PDGFR-β activity. cyy260 causes DNA damage and induces apoptosis in osteosarcoma cells. cyy260 inhibits PDGFR-β expression and demonstrates the ability to inhibit tumor migration. cyy260 exhibits excellent anti-osteosarcoma activity in vitro and in vivo. cyy260 could be a potential PDGFR-β small molecule inhibitor for the treatment of osteosarcoma.