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.
Conclusion:
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / pharmacology
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Abietanes / antagonists & inhibitors
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Abietanes / pharmacology*
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Antineoplastic Agents, Phytogenic / antagonists & inhibitors
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Antineoplastic Agents, Phytogenic / pharmacology*
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Apoptosis / drug effects
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Apoptosis Regulatory Proteins / genetics*
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Apoptosis Regulatory Proteins / metabolism
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Autophagy / drug effects
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Beclin-1
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Cyclin-Dependent Kinase Inhibitor p27 / genetics
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Cyclin-Dependent Kinase Inhibitor p27 / metabolism
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DNA Damage
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Female
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Free Radical Scavengers / pharmacology
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G2 Phase Cell Cycle Checkpoints / drug effects
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Humans
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Membrane Potential, Mitochondrial / drug effects
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Membrane Proteins / genetics*
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Membrane Proteins / metabolism
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / metabolism
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Phosphorylation / drug effects
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Reactive Oxygen Species / metabolism*
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Triple Negative Breast Neoplasms / genetics
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Triple Negative Breast Neoplasms / metabolism
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Triple Negative Breast Neoplasms / pathology
Substances
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Abietanes
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Antineoplastic Agents, Phytogenic
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Apoptosis Regulatory Proteins
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BECN1 protein, human
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Beclin-1
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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Free Radical Scavengers
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Membrane Proteins
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Reactive Oxygen Species
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Cyclin-Dependent Kinase Inhibitor p27
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carnosol
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1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt
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MAPK1 protein, human
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
Grants and funding
This work was supported by UAEU Program for Advanced Research (Grant 31S111-UPAR) and the Faculty of Science interdisciplinary research grant UAE University (Grant 31S033-FOS) to Rabah Iratni. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.