title: Desacetyl nimbinene inhibits breast cancer growth and metastasis through reactive oxygen species mediated mechanisms.
abstract: Accumulation of reactive oxygen species (ROS) has been implicated in induction of apoptosis and regulation of key signaling molecules in cancer cells. Phytochemicals are potent source of anticancer drugs as wells as potential inducers of ROS. Neem (Azadirachta indica) is a medicinal plant used for the treatment of various diseases. The main objective of this study is to investigate the anticancer effect of desacetyl nimbinene (DAN; an active ingredient of neem) against breast cancer. Normal and breast cancer cell lines were used for the study. The effect of DAN on cell proliferation, apoptosis, ROS generation, migration, and invasion was analyzed. Antioxidant enzymes superoxide dismutase (SOD)1 and SOD2 were overexpressed to test the effect of DAN-induced ROS generation on breast cancer growth. Key survival and apoptotic protein markers were analyzed to validate the anticancer effect of DAN. Our data demonstrated that DAN inhibited the growth of breast cancer cells by inducing ROS generation. Further investigations revealed that DAN treatment lead to the loss of mitochondrial membrane potential resulting in mitochondria-dependent apoptotic cell death. Increased phosphorylation of c-Jun-N-terminal kinase (JNK) and reduced phosphorylation of p38 were also observed in response to DAN treatment. Inhibition of ROS production by overexpressing antioxidant enzymes SOD1 and SOD2 reduced the DAN-induced cytotoxicity. Additionally, DAN significantly inhibited migration and invasion of MDA-MB-231 breast cancer cells. Overall, our data suggest that DAN exerts its anticancer effect on breast cancer by induction of mitochondria-mediated apoptosis mediated by ROS accumulation.
authors.affiliation: Center of Emphasis in Cancer Research, Department of Biomedical Sciences, Paul L Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA.
authors.forename: Arunkumar
authors.initials: A
authors.lastname: Arumugam
authors.affiliation: Center of Emphasis in Cancer Research, Department of Biomedical Sciences, Paul L Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA.
authors.forename: Ramadevi
authors.initials: R
authors.lastname: Subramani
authors.affiliation: Center of Emphasis in Cancer Research, Department of Biomedical Sciences, Paul L Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA.
authors.forename: Sushmita
authors.initials: S
authors.lastname: Nandy
authors.affiliation: Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Powell
authors.affiliation: Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA.
authors.forename: Marissa
authors.initials: M
authors.lastname: Velazquez
authors.affiliation: Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA.
authors.forename: Alexis
authors.initials: A
authors.lastname: Orozco
authors.affiliation: Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Galvez
authors.affiliation: Center of Emphasis in Cancer Research, Department of Biomedical Sciences, Paul L Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA. rajkumar.lakshmanaswamy@ttuhsc.edu.|Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA. rajkumar.lakshmanaswamy@ttuhsc.edu.
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Lakshmanaswamy
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002374:Catalase / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D002470:Cell Survival; D005260:Female; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D002374:Catalase; D013482:Superoxide Dismutase
keywords: Apoptosis; Breast cancer; Desacetyl nimbinene; Neem; ROS; SOD