title: Phyllanthus urinaria's Inhibition of Human Osteosarcoma Xenografts Growth in Mice is Associated with Modulation of Mitochondrial Fission/Fusion Machinery.
abstract: Osteosarcoma is an aggressive bone cancer arising from primitive transformed cells of mesenchymal origin to form malignant osteoid. Phyllanthus urinaria [Formula: see text]P. urinaria[Formula: see text] is a widely used folk medicine in cancer treatment, however the mechanism of P. urinaria inhibited human osteosarcoma is unclear. The present study was aimed at investigating the antitumoral effects of an aqueous P. urinaria on human osteosarcoma in vivo and the related underlying mechanisms, mainly focusing on mitochondrial dynamic dysfunction. Our results showed that oral administration of P. urinaria to mice led to significant inhibition of tumor development without substantial changes to body weight or major organs. Histological examinations with H&E, Giemsa, and Masson trichrome stains confirmed inhibition of tumor growth by the P. urinaria treatment. Immunohistochemical staining of proliferation markers antigen KI-67 (Ki67) and proliferating cell nuclear antigen (PCNA), as well as a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay demonstrated a decrease of tumor proliferation and an increase of apoptosis, which was associated with the modulation of B-cell lymphoma 2 (Bcl-2) family activating the caspase cascade in the P. urinaria-treated mice. The neovascularization marker cluster of differentiation 31 (CD31) was inhibited in P. urinaria-treated xenografts, implicating the potential anti-angiogenic effect of P. urinaria. P. urinaria treatment resulted in a significant decrease in the mitochondrial fusion proteins, including mitofusin 1/2 (Mfn1/2) and optic atrophy type 1 (Opa1), as well as an increase in the fission protein dynamin-related protein 1 (Drp1). The results of this study suggest mitochondrial dysfunction is associated with dynamic change that is involved in the apoptosis and anti-angiogenesis elicited by P. urinaria.
authors: * Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan.|† School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan.
authors: Sheng-Teng
authors: ST
authors: Huang
authors: ‡ Division of General Surgery, Ministry of Health and Welfare Pingtung Hospital, Pingtung, Taiwan.
authors: Chao-Chun
authors: CC
authors: Huang
authors: § Department of Chinese Medicine and Mitochondrial Research Unit, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors: Jer-Ming
authors: JM
authors: Sheen
authors: ** Department of Neurology and Mitochondrial Research Unit, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors: Tsu-Kung
authors: TK
authors: Lin
authors: ** Department of Neurology and Mitochondrial Research Unit, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors: Pei-Lin
authors: PL
authors: Liao
authors: ** Department of Neurology and Mitochondrial Research Unit, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors: Wen-Liang
authors: WL
authors: Huang
authors: ¶ Department of Internal Medicine and Mitochondrial Research Unit, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors: Pei-Wen
authors: PW
authors: Wang
authors: ** Department of Neurology and Mitochondrial Research Unit, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors: Chia-Wei
authors: CW
authors: Liou
authors: ∥ Division of Pediatric Surgery and Mitochondrial Research Unit, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors: Jiin-Haur
authors: JH
authors: Chuang
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics*; D004253:DNA Nucleotidylexotransferase / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D063154:Mitochondrial Dynamics / Q000187:drug effects* / Q000235:genetics*; D009368:Neoplasm Transplantation; D010020:Osteonecrosis / Q000235:genetics* / Q000473:pathology*; D012516:Osteosarcoma / Q000235:genetics* / Q000473:pathology*; D029803:Phyllanthus / Q000737:chemistry*; D008517:Phytotherapy; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D019394:Ki-67 Antigen; D010936:Plant Extracts; D018809:Proliferating Cell Nuclear Antigen; D004253:DNA Nucleotidylexotransferase
keywords: Angiogenesis; Apoptosis; Mitochondrial Dynamics; Phyllanthus urinaria