Cannabidiol induces programmed cell death in breast cancer cells by coordinating the crosstalk between apoptosis and autophagy

Cannabidiol (CBD), a major non-psychoactive constituent of cannabis, is considered an anti-neoplastic agent based on 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 demonstrated 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 demonstrated that CBD induces ER stress, and subsequently inhibits AKT and mTOR signaling as shown by decreased levels of phosphorylated mTOR and 4EBP1, and Cyclin D1. Analyzing further the crosstalk 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. Namely, while 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 highlights the value of continued investigation into the potential use of CBD as an anti-neoplastic agent.

- Shrivastava, A., Kuzontkoski, P. M., Groopman, J. et al. (May 2011) Cannabidiol induces programmed cell death in breast cancer cells by coordinating the crosstalk between apoptosis and autophagy [Abstract] Molecular Cancer Therapeutics published online. DOI:10.1158/1535-7163.MCT-10-1100

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