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Protein Kinase B and Extracellular Signal-Regulated Kinase Inactivation is Associated with Regorafenib-Induced Inhibition of Osteosarcoma Progression In Vitro and In Vivo

by 1,2, 3,4,5,*,† and 6,*,†
1
Department of Physical Medicine and Rehabilitation, National Yang-Ming University Hospital, Yilan 260, Taiwan
2
Department of Medicine, National Yang-Ming University, Taipei 112, Taiwan
3
Department of Radiation Oncology, Chang Bing Show Chwan Memorial Hospital, Changhua 505, Taiwan
4
Department of Radiation Oncology, Show Chwan Memorial Hospital, Changhua 500, Taiwan
5
Department of Medical Imaging and Radiological Sciences, Central Taiwan University of Science and Technology, Taichung 406, Taiwan
6
Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan
*
Authors to whom correspondence should be addressed.
Authors contributed equally.
J. Clin. Med. 2019, 8(6), 900; https://doi.org/10.3390/jcm8060900
Received: 13 May 2019 / Revised: 17 June 2019 / Accepted: 20 June 2019 / Published: 24 June 2019
(This article belongs to the Section Clinical Cytology)
Osteosarcoma is the most common type of bone cancer. Multimodality treatment involving chemotherapy, radiotherapy and surgery is not effective enough to control osteosarcoma. Regorafenib, the oral multi-kinase inhibitor, has been shown to have positive efficacy on disease progression delay in chemotherapy resistant osteosarcoma patients. However anti-cancer effect and mechanism of regorafenib in osteosarcoma is ambiguous. Thus, the aim of this study is to investigate the efficacy and molecular mechanism of regorafenib on osteosarcoma in vitro and in vivo. Human osteosarcomas U-2 OS or MG-63 were treated with regorafenib, miltefosine (protein kinase B (AKT) inhibitor), or PD98059 (mitogen-activated protein/extracellular signal-regulated kinase (MEK) pathway inhibitor) for 24 or 48 h. Cell viability, apoptotic signaling transduction, tumor invasion, expression of tumor progression-associated proteins and tumor growth after regorafenib treatment were assayed by MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, flow cytometry, transwell assay, Western blotting assay and in vivo animal experiment, respectively. In these studies, we also indicated that regorafenib suppressed cell growth by prompting apoptosis of osteosarcoma cells, which is mediated through inactivation of ERK and AKT signaling pathways. After regorafenib treatment, downregulation of related genes in invasion (vascular endothelial growth factor (VEGF) and matrix metallopeptidase 9 (MMP-9)), proliferation (CyclinD1) and anti-apoptosis (X-linked inhibitor of apoptosis protein (XIAP), myeloid cell leukemia-1 (MCL-1), and cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (C-FLIP)) were found. Moreover, upregulation of caspase-3 and caspase-8 cleavage were also observed. In sum, we suggest that regorafenib has potential to suppress osteosarcoma progression via inactivation of AKT and ERK mediated signaling pathway. View Full-Text
Keywords: regorafenib; osteosarcoma; AKT; ERK regorafenib; osteosarcoma; AKT; ERK
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MDPI and ACS Style

Pan, P.-J.; Liu, Y.-C.; Hsu, F.-T. Protein Kinase B and Extracellular Signal-Regulated Kinase Inactivation is Associated with Regorafenib-Induced Inhibition of Osteosarcoma Progression In Vitro and In Vivo. J. Clin. Med. 2019, 8, 900. https://doi.org/10.3390/jcm8060900

AMA Style

Pan P-J, Liu Y-C, Hsu F-T. Protein Kinase B and Extracellular Signal-Regulated Kinase Inactivation is Associated with Regorafenib-Induced Inhibition of Osteosarcoma Progression In Vitro and In Vivo. Journal of Clinical Medicine. 2019; 8(6):900. https://doi.org/10.3390/jcm8060900

Chicago/Turabian Style

Pan, Po-Jung, Yu-Chang Liu, and Fei-Ting Hsu. 2019. "Protein Kinase B and Extracellular Signal-Regulated Kinase Inactivation is Associated with Regorafenib-Induced Inhibition of Osteosarcoma Progression In Vitro and In Vivo" Journal of Clinical Medicine 8, no. 6: 900. https://doi.org/10.3390/jcm8060900

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