title: Nimbolide Induces ROS-Regulated Apoptosis and Inhibits Cell Migration in Osteosarcoma.
abstract: Osteosarcoma (OS) is a primary malignant tumor of bone and is most prevalent in children and adolescents. OS is frequently associated with pulmonary metastasis, which is the main cause of OS-related mortality. OS has a poor prognosis and is often unresponsive to conventional chemotherapy. In this study, we determined that Nimbolide, a novel anti-cancer therapy, acts by modulating multiple mechanisms in osteosarcoma cells. Nimbolide induces apoptosis by increasing endoplasmic reticulum (ER) stress, mitochondrial dysfunction, accumulation of reactive oxygen species (ROS), and finally, caspase activation. We also determined that Nimbolide inhibits cell migration, which is crucial for metastasis, by reducing the expression of integrin αvβ5. In addition, our results demonstrate that integrin αvβ5 expression is modulated by the PI3K/Akt and NF-κB signaling cascade. Nimbolide has potential as an anti-tumor drug given its multifunctional effects in OS. Collectively, these results help us to understand the mechanisms of action of Nimbolide and will aid in the development of effective therapies for OS.
authors.affiliation: Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei 11101, Taiwan. anti0822@hotmail.com.
authors.forename: Ju-Fang
authors.initials: JF
authors.lastname: Liu
authors.affiliation: Department of Orthopedic Surgery, National Taiwan University Hospital, Taipei 10617, Taiwan. chhou@ntu.edu.tw.
authors.forename: Chun-Han
authors.initials: CH
authors.lastname: Hou
authors.affiliation: Department of Dermatology, Sijhih Cathay General Hospital, Taipei 22174, Taiwan. lavande213@gmail.com.
authors.forename: Feng-Ling
authors.initials: FL
authors.lastname: Lin
authors.affiliation: Department of Orthopedic Surgery, National Taiwan University Hospital, Taipei 10617, Taiwan. m102094011@tmu.edu.tw.
authors.forename: Ya-Ting
authors.initials: YT
authors.lastname: Tsao
authors.affiliation: Department of Orthopedic Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, No. 95, Wenchang Road, Shilin District, Taipei 11101, Taiwan. shengmou@ms.skh.org.tw.
authors.forename: Sheng-Mou
authors.initials: SM
authors.lastname: Hou
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D036701:Limonins / Q000737:chemistry / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D012516:Osteosarcoma / Q000378:metabolism* / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019030:Receptors, Vitronectin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D036701:Limonins; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; C042198:nimbolide; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; D002118:Calcium
keywords: apoptosis; endoplasmic reticulum stress; migration; osteosarcoma; reactive oxygen species