title: Nimbolide inhibits pancreatic cancer growth and metastasis through ROS-mediated apoptosis and inhibition of epithelial-to-mesenchymal transition.
abstract: The mortality and morbidity rates of pancreatic cancer are high because of its extremely invasive and metastatic nature. Its lack of symptoms, late diagnosis and chemo-resistance and the ineffective treatment modalities warrant the development of new chemo-therapeutic agents for pancreatic cancer. Agents from medicinal plants have demonstrated therapeutic benefits in various human cancers. Nimbolide, an active molecule isolated from Azadirachta indica, has been reported to exhibit several medicinal properties. This study assessed the anticancer properties of nimbolide against pancreatic cancer. Our data reveal that nimbolide induces excessive generation of reactive oxygen species (ROS), thereby regulating both apoptosis and autophagy in pancreatic cancer cells. Experiments with the autophagy inhibitors 3-methyladenine and chloroquine diphosphate salt and the apoptosis inhibitor z-VAD-fmk demonstrated that nimbolide-mediated ROS generation inhibited proliferation (through reduced PI3K/AKT/mTOR and ERK signaling) and metastasis (through decreased EMT, invasion, migration and colony forming abilities) via mitochondrial-mediated apoptotic cell death but not via autophagy. In vivo experiments also demonstrated that nimbolide was effective in inhibiting pancreatic cancer growth and metastasis. Overall, our data suggest that nimbolide can serve as a potential chemo-therapeutic agent for pancreatic cancer.
authors.affiliation: Center of Excellence in Cancer Research, Department of Biomedical Sciences MSB1, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, Texas-79905.
authors.forename: Ramadevi
authors.initials: R
authors.lastname: Subramani
authors.affiliation: Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, Texas-79905.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Gonzalez
authors.affiliation: Center of Excellence in Cancer Research, Department of Biomedical Sciences MSB1, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, Texas-79905.
authors.forename: Arunkumar
authors.initials: A
authors.lastname: Arumugam
authors.affiliation: Center of Excellence in Cancer Research, Department of Biomedical Sciences MSB1, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, Texas-79905.
authors.forename: Sushmita
authors.initials: S
authors.lastname: Nandy
authors.affiliation: The University of Texas at El Paso, El Paso, TX 79968.
authors.forename: Viviana
authors.initials: V
authors.lastname: Gonzalez
authors.affiliation: Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, Texas-79905.
authors.forename: Joshua
authors.initials: J
authors.lastname: Medel
authors.affiliation: Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, Texas-79905.
authors.forename: Fernando
authors.initials: F
authors.lastname: Camacho
authors.affiliation: The University of Texas at El Paso, El Paso, TX 79968.
authors.forename: Andrew
authors.initials: A
authors.lastname: Ortega
authors.affiliation: Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, Texas-79905.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Bonkoungou
authors.affiliation: The University of Texas at El Paso, El Paso, TX 79968.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Narayan
authors.affiliation: Biostatistics and Epidemiology Consulting Laboratory, Texas Tech University Health Sciences Center, El Paso, Texas-79905.
authors.forename: Alok kumar
authors.initials: Ak
authors.lastname: Dwivedi
authors.affiliation: Center of Excellence in Cancer Research, Department of Biomedical Sciences MSB1, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, Texas-79905.|Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, Texas-79905.
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Lakshmanaswamy
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006801:Humans; D036701:Limonins / Q000008:administration & dosage*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D036701:Limonins; D017382:Reactive Oxygen Species; C042198:nimbolide; C025946:3-methyladenine; D019869:Phosphatidylinositol 3-Kinases; D000225:Adenine