Weijie Chen1,2,3, Su Wu4, Yang Huang3, Tingting Zhang5, Hao Dong6, Xing Zheng3, Tao Chen3, Xiaokang Gong3, Gang Liu1,2, Xing Zhao1. 1. Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, HangZhou, People's Republic of China. 2. Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, HangZhou, People's Republic of China. 3. Department of Orthopedics, Taizhou Municipal Hospital, Taizhou, People's Republic of China. 4. Department of Orthopedics, The Third People's Hospital of JingDeZhen, JingDeZhen, People's Republic of China. 5. Taizhou Public Security Supervision Hospital, Taizhou Municipal Hospital, Taizhou, People's Republic of China. 6. Department of Gastrointestinal Surgery, Taizhou Municipal Hospital, Taizhou, People's Republic of China.
Abstract
INTRODUCTION: Osteosarcoma is the most common primary malignancy of the bone among adolescents and children. Despite intensive chemotherapy and aggressive surgery, the 5-year survival rate of osteosarcoma still falls under 70%, mainly due to its tendency to metastasize and to develop drug resistance. Therefore, new treatments for osteosarcoma are urgently needed. HGF/c-Met signaling pathway, when dysregulated, is involved in the onset, progression and metastasis of various cancers, making the HGF/c-Met axis a promising therapeutic target. METHODS: In this study, we found Met to be a cancer-promoting gene in osteosarcoma as well, and aimed to investigate the role of a c-met inhibitor (PHA-665752) in osteosarcoma. For this purpose, two human osteosarcoma cell lines (143B and U2OS) were introduced in this study and treated with PHA-665752. CCK8 cell proliferation assay was performed to obtain the IC50 value of PHA-665752 for 143B and U2OS. After that, colony formation assay, transwell migration and invasion assay and wound-healing assay were performed. Furthermore, a tumor-transplanted mouse model was used for in vivo experiments. RESULTS: Our results showed that PHA-665752 could suppress osteosarcoma progression, promote apoptosis and inhibit proliferation of human osteosarcoma cells. Moreover, we found ERK1/2 pathway to be an important mediator underlying the osteosarcoma-suppressing function of PHA-665752. LY3214996, a highly selective inhibitor of the ERK1/2 pathway, was able to antagonize the effects of PHA-665752 in osteosarcoma. Finally, in vivo experiments indicated that PHA-665752 suppressed tumor growth in a tumor-transplanted mouse model. CONCLUSION: Taken together, Met provided a druggable target for osteosarcoma and PHA-665752 is a promising candidate for anti-osteosarcoma treatments.
INTRODUCTION: Osteosarcoma is the most common primary malignancy of the bone among adolescents and children. Despite intensive chemotherapy and aggressive surgery, the 5-year survival rate of osteosarcoma still falls under 70%, mainly due to its tendency to metastasize and to develop drug resistance. Therefore, new treatments for osteosarcoma are urgently needed. HGF/c-Met signaling pathway, when dysregulated, is involved in the onset, progression and metastasis of various cancers, making the HGF/c-Met axis a promising therapeutic target. METHODS: In this study, we found Met to be a cancer-promoting gene in osteosarcoma as well, and aimed to investigate the role of a c-met inhibitor (PHA-665752) in osteosarcoma. For this purpose, two human osteosarcoma cell lines (143B and U2OS) were introduced in this study and treated with PHA-665752. CCK8 cell proliferation assay was performed to obtain the IC50 value of PHA-665752 for 143B and U2OS. After that, colony formation assay, transwell migration and invasion assay and wound-healing assay were performed. Furthermore, a tumor-transplanted mouse model was used for in vivo experiments. RESULTS: Our results showed that PHA-665752 could suppress osteosarcoma progression, promote apoptosis and inhibit proliferation of human osteosarcoma cells. Moreover, we found ERK1/2 pathway to be an important mediator underlying the osteosarcoma-suppressing function of PHA-665752. LY3214996, a highly selective inhibitor of the ERK1/2 pathway, was able to antagonize the effects of PHA-665752 in osteosarcoma. Finally, in vivo experiments indicated that PHA-665752 suppressed tumor growth in a tumor-transplanted mouse model. CONCLUSION: Taken together, Met provided a druggable target for osteosarcoma and PHA-665752 is a promising candidate for anti-osteosarcoma treatments.
Authors: Tamer Refaat; Eric D Donnelly; Sean Sachdev; Vamsi Parimi; Samar El Achy; Prarthana Dalal; Mohamed Farouk; Natasha Berg; Irene Helenowski; Jeffrey P Gross; John Lurain; Jonathan B Strauss; Gayle Woloschak; Jian-Jun Wei; William Small Journal: Am J Clin Oncol Date: 2017-12 Impact factor: 2.339
Authors: Richard Gorlick; Peter Anderson; Irene Andrulis; Carola Arndt; G Peter Beardsley; Mark Bernstein; Julia Bridge; Nai-Kong Cheung; Jeffrey S Dome; David Ebb; Thomas Gardner; Mark Gebhardt; Holcombe Grier; Marc Hansen; John Healey; Lee Helman; Janet Hock; Janet Houghton; Peter Houghton; Andrew Huvos; Chand Khanna; Mark Kieran; Eugenie Kleinerman; Marc Ladanyi; Ching Lau; David Malkin; Neyssa Marina; Paul Meltzer; Paul Meyers; Deborah Schofield; Cindy Schwartz; Malcolm A Smith; Jeffrey Toretsky; Maria Tsokos; Leonard Wexler; Jon Wigginton; Stephen Withrow; Mason Schoenfeldt; Barry Anderson Journal: Clin Cancer Res Date: 2003-11-15 Impact factor: 12.531