Carnosol induces ROS-mediated beclin1-independent autophagy and apoptosis in triple negative breast cancer

• Published in: PloS one Vol. 9; no. 10; p. e109630
• Main Authors: Al Dhaheri, Yusra, Attoub, Samir, Ramadan, Gaber, Arafat, Kholoud, Bajbouj, Khuloud, Karuvantevida, Noushad, AbuQamar, Synan, Eid, Ali, Iratni, Rabah
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.10.2014; Public Library of Science (PLoS)
• Subjects: 1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt - pharmacology; Anticancer properties; Antineoplastic Agents, Phytogenic - antagonists & inhibitors; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Autophagy; Autophagy - drug effects; Beclin-1; Biology; Biology and Life Sciences; Breast cancer; Cancer; Cancer therapies; Cell cycle; Cell death; Cell Line, Tumor; Cell Proliferation - drug effects; Coexistence; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cyclin-Dependent Kinase Inhibitor p27 - genetics; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Cytotoxicity; Damage detection; Deoxyribonucleic acid; Diterpenes, Abietane - antagonists & inhibitors; Diterpenes, Abietane - pharmacology; DNA; DNA Damage; Drugs; Extracellular signal-regulated kinase; Female; Free Radical Scavengers - pharmacology; G2 Phase Cell Cycle Checkpoints - drug effects; Gene expression; Health sciences; Homeostasis; Humans; In vivo methods and tests; Leukemia; Medical prognosis; Medicine and Health Sciences; Membrane Potential, Mitochondrial - drug effects; Membrane Proteins - genetics; Membrane Proteins - metabolism; Micrography; Mitochondrial DNA; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; Oxygen; Phagocytosis; Phosphorylation - drug effects; Phytochemicals; Reactive oxygen species; Reactive Oxygen Species - metabolism; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Viability; United States > US; Qatar; United Arab Emirates
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0109630

In this study we investigated the in vitro and in vivo anticancer effect of carnosol, a naturally occurring polyphenol, in triple negative breast cancer. 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. 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.