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Molecular Cancer Therapeutics
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Therapeutic Discovery

Cannabidiol Induces Programmed Cell Death in Breast Cancer Cells by Coordinating the Cross-talk between Apoptosis and Autophagy

Ashutosh Shrivastava, Paula M. Kuzontkoski, Jerome E. Groopman and Anil Prasad
Ashutosh Shrivastava
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Paula M. Kuzontkoski
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Jerome E. Groopman
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Anil Prasad
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DOI: 10.1158/1535-7163.MCT-10-1100 Published July 2011
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Abstract

Cannabidiol (CBD), a major nonpsychoactive constituent of cannabis, is considered an antineoplastic agent on the basis of its in vitro and in vivo activity against tumor cells. However, the exact molecular mechanism through which CBD mediates this activity is yet to be elucidated. Here, we have shown CBD-induced cell death of breast cancer cells, independent of cannabinoid and vallinoid receptor activation. Electron microscopy revealed morphologies consistent with the coexistence of autophagy and apoptosis. Western blot analysis confirmed these findings. We showed that CBD induces endoplasmic reticulum stress and, subsequently, inhibits AKT and mTOR signaling as shown by decreased levels of phosphorylated mTOR and 4EBP1, and cyclin D1. Analyzing further the cross-talk between the autophagic and apoptotic signaling pathways, we found that beclin1 plays a central role in the induction of CBD-mediated apoptosis in MDA-MB-231 breast cancer cells. Although CBD enhances the interaction between beclin1 and Vps34, it inhibits the association between beclin1 and Bcl-2. In addition, we showed that CBD reduces mitochondrial membrane potential, triggers the translocation of BID to the mitochondria, the release of cytochrome c to the cytosol, and, ultimately, the activation of the intrinsic apoptotic pathway in breast cancer cells. CBD increased the generation of reactive oxygen species (ROS), and ROS inhibition blocked the induction of apoptosis and autophagy. Our study revealed an intricate interplay between apoptosis and autophagy in CBD-treated breast cancer cells and highlighted the value of continued investigation into the potential use of CBD as an antineoplastic agent. Mol Cancer Ther; 10(7); 1161–72. ©2011 AACR.

Footnotes

  • Note: Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Received December 9, 2010.
  • Revision received April 4, 2011.
  • Accepted April 28, 2011.
  • ©2011 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 10 (7)
July 2011
Volume 10, Issue 7
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Cannabidiol Induces Programmed Cell Death in Breast Cancer Cells by Coordinating the Cross-talk between Apoptosis and Autophagy
Ashutosh Shrivastava, Paula M. Kuzontkoski, Jerome E. Groopman and Anil Prasad
Mol Cancer Ther July 1 2011 (10) (7) 1161-1172; DOI: 10.1158/1535-7163.MCT-10-1100

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Cannabidiol Induces Programmed Cell Death in Breast Cancer Cells by Coordinating the Cross-talk between Apoptosis and Autophagy
Ashutosh Shrivastava, Paula M. Kuzontkoski, Jerome E. Groopman and Anil Prasad
Mol Cancer Ther July 1 2011 (10) (7) 1161-1172; DOI: 10.1158/1535-7163.MCT-10-1100
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Molecular Cancer Therapeutics
eISSN: 1538-8514
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