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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Cancer Therapeutic Insights

COX-2 and PPAR-γ Confer Cannabidiol-Induced Apoptosis of Human Lung Cancer Cells

Robert Ramer, Katharina Heinemann, Jutta Merkord, Helga Rohde, Achim Salamon, Michael Linnebacher and Burkhard Hinz
Robert Ramer
1Institute of Toxicology and Pharmacology; 2Department of Cell Biology; and 3Section of Molecular Oncology and Immunotherapy, Department of General Surgery, University of Rostock, Rostock, Germany
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Katharina Heinemann
1Institute of Toxicology and Pharmacology; 2Department of Cell Biology; and 3Section of Molecular Oncology and Immunotherapy, Department of General Surgery, University of Rostock, Rostock, Germany
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Jutta Merkord
1Institute of Toxicology and Pharmacology; 2Department of Cell Biology; and 3Section of Molecular Oncology and Immunotherapy, Department of General Surgery, University of Rostock, Rostock, Germany
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Helga Rohde
1Institute of Toxicology and Pharmacology; 2Department of Cell Biology; and 3Section of Molecular Oncology and Immunotherapy, Department of General Surgery, University of Rostock, Rostock, Germany
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Achim Salamon
1Institute of Toxicology and Pharmacology; 2Department of Cell Biology; and 3Section of Molecular Oncology and Immunotherapy, Department of General Surgery, University of Rostock, Rostock, Germany
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Michael Linnebacher
1Institute of Toxicology and Pharmacology; 2Department of Cell Biology; and 3Section of Molecular Oncology and Immunotherapy, Department of General Surgery, University of Rostock, Rostock, Germany
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Burkhard Hinz
1Institute of Toxicology and Pharmacology; 2Department of Cell Biology; and 3Section of Molecular Oncology and Immunotherapy, Department of General Surgery, University of Rostock, Rostock, Germany
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DOI: 10.1158/1535-7163.MCT-12-0335 Published January 2013
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Abstract

The antitumorigenic mechanism of cannabidiol is still controversial. This study investigates the role of COX-2 and PPAR-γ in cannabidiol's proapoptotic and tumor-regressive action. In lung cancer cell lines (A549, H460) and primary cells from a patient with lung cancer, cannabidiol elicited decreased viability associated with apoptosis. Apoptotic cell death by cannabidiol was suppressed by NS-398 (COX-2 inhibitor), GW9662 (PPAR-γ antagonist), and siRNA targeting COX-2 and PPAR-γ. Cannabidiol-induced apoptosis was paralleled by upregulation of COX-2 and PPAR-γ mRNA and protein expression with a maximum induction of COX-2 mRNA after 8 hours and continuous increases of PPAR-γ mRNA when compared with vehicle. In response to cannabidiol, tumor cell lines exhibited increased levels of COX-2–dependent prostaglandins (PG) among which PGD2 and 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) caused a translocation of PPAR-γ to the nucleus and induced a PPAR-γ–dependent apoptotic cell death. Moreover, in A549-xenografted nude mice, cannabidiol caused upregulation of COX-2 and PPAR-γ in tumor tissue and tumor regression that was reversible by GW9662. Together, our data show a novel proapoptotic mechanism of cannabidiol involving initial upregulation of COX-2 and PPAR-γ and a subsequent nuclear translocation of PPAR-γ by COX-2–dependent PGs. Mol Cancer Ther; 12(1); 69–82. ©2012 AACR.

  • Received April 24, 2012.
  • Revision received September 14, 2012.
  • Accepted November 4, 2012.
  • ©2012 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 12 (1)
January 2013
Volume 12, Issue 1
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COX-2 and PPAR-γ Confer Cannabidiol-Induced Apoptosis of Human Lung Cancer Cells
Robert Ramer, Katharina Heinemann, Jutta Merkord, Helga Rohde, Achim Salamon, Michael Linnebacher and Burkhard Hinz
Mol Cancer Ther January 1 2013 (12) (1) 69-82; DOI: 10.1158/1535-7163.MCT-12-0335

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COX-2 and PPAR-γ Confer Cannabidiol-Induced Apoptosis of Human Lung Cancer Cells
Robert Ramer, Katharina Heinemann, Jutta Merkord, Helga Rohde, Achim Salamon, Michael Linnebacher and Burkhard Hinz
Mol Cancer Ther January 1 2013 (12) (1) 69-82; DOI: 10.1158/1535-7163.MCT-12-0335
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Molecular Cancer Therapeutics
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