Carnosol Induces ROS-Mediated Beclin1-Independent Autophagy and Apoptosis in Triple Negative Breast Cancer |
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Authors: | Yusra Al Dhaheri Samir Attoub Gaber Ramadan Kholoud Arafat Khuloud Bajbouj Noushad Karuvantevida Synan AbuQamar Ali Eid Rabah Iratni |
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Affiliation: | 1. Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates.; 2. Department of Pharmacology & Therapeutics, Faculty of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.; 3. Department of Biological and Environmental Sciences, College of Arts and Sciences, Qatar University, Doha, Qatar.; Toho University School of Medicine, Japan, |
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Abstract: | BackgroundIn this study we investigated the in vitro and in vivo anticancer effect of carnosol, a naturally occurring polyphenol, in triple negative breast cancer.ResultsWe 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.ConclusionIn 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. |
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