title: Carnosol induces ROS-mediated beclin1-independent autophagy and apoptosis in triple negative breast cancer.
abstract: BACKGROUND
  In this study we investigated the in vitro and in vivo anticancer effect of carnosol, a naturally occurring polyphenol, in triple negative breast cancer.
  
  
  RESULTS
  We found that carnosol significantly inhibited the viability and colony growth induced G2 arrest in the triple negative MDA-MB-231. Blockade of the cell cycle was associated with increased p21/WAF1 expression and downregulation of p27. Interestingly, carnosol was found to induce beclin1-independent autophagy and apoptosis in MDA-MB-231 cells. The coexistence of both events, autophagy and apoptosis, was confirmed by electron micrography. Induction of autophagy was found to be an early event, detected within 3 h post-treatment, which subsequently led to apoptosis. Carnosol treatment also caused a dose-dependent increase in the levels of phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2). Moreover, we show that carnosol induced DNA damage, reduced the mitochondrial potential and triggered the activation of the intrinsic and extrinsic apoptotic pathway. Furthermore, we found that carnosol induced a dose-dependent generation of reactive oxygen species (ROS) and inhibition of ROS by tiron, a ROS scavenger, blocked the induction of autophagy and apoptosis and attenuated DNA damage. To our knowledge, this is the first report to identify the induction of autophagy by carnosol.
  
  
  CONCLUSIONS
  In conclusion our findings provide strong evidence that carnosol may be an alternative therapeutic candidate against the aggressive form of breast cancer and hence deserves more exploration.
authors.affiliation: Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Yusra
authors.initials: Y
authors.lastname: Al Dhaheri
authors.affiliation: Department of Pharmacology & Therapeutics, Faculty of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Samir
authors.initials: S
authors.lastname: Attoub
authors.affiliation: Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Gaber
authors.initials: G
authors.lastname: Ramadan
authors.affiliation: Department of Pharmacology & Therapeutics, Faculty of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Kholoud
authors.initials: K
authors.lastname: Arafat
authors.affiliation: Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Khuloud
authors.initials: K
authors.lastname: Bajbouj
authors.affiliation: Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Noushad
authors.initials: N
authors.lastname: Karuvantevida
authors.affiliation: Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Synan
authors.initials: S
authors.lastname: AbuQamar
authors.affiliation: Department of Biological and Environmental Sciences, College of Arts and Sciences, Qatar University, Doha, Qatar.
authors.forename: Ali
authors.initials: A
authors.lastname: Eid
authors.affiliation: Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Rabah
authors.initials: R
authors.lastname: Iratni
mesh_terms: D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / Q000494:pharmacology; D045784:Abietanes / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D000071186:Beclin-1; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D045784:Abietanes; D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016166:Free Radical Scavengers; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D050760:Cyclin-Dependent Kinase Inhibitor p27; C068623:carnosol; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3