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.
Data synthesis: Cannabis and cannabinoid effectiveness can be attributed to active components delta-9-tetrahydrocannabinol and cannabidiol. Multiple dosage forms exist, each with different properties contributing to efficacy and safety differences. No data supports use as anticancer agents, and mixed efficacy results have been reported when used in cancer patients with nausea, pain, and anorexia. Inclusion of medicinal and synthetic products, small sample sizes, varying patient populations, and different dosage forms, doses, and drug combinations. These products are well tolerated, and adverse effects depend on the main active component.
Objective: To review pharmacology, available dosage forms, efficacy, and safety of cannabis and cannabinoids in cancer patients.
Relevance to patient care and clinical practice: Healthcare professionals need to identify appropriateness, monitor, and document use of cannabis and cannabinoids similar to other drug therapies as well as educate the patients/ caregivers about potential benefits and risks.
Data sources: In PubMed (1965 to June 2020) the search was conducted using the search terms cannabidiol, cannabis, CBD, dronabinol, endocannabinoids, medical marijuana, nabiximols, nabilone, THC, and cancer. Abstracts from article bibliographies were reviewed.
Conclusions: Current evidence for use of medical cannabis and cannabinoids in cancer patients is weak. However, healthcare professionals are in an ideal role to monitor and educate patients using medical cannabis and cannabinoids.
Study selection and data extraction: Relevant English-language studies conducted in humans evaluating cannabis and cannabinoids for cancer treatment or related symptoms were considered. Reference lists in relevant articles, package inserts, guidance documents, and addditional articles evaluating cannabis and cannabinoids were identified.
Keywords: cancer; cannabis; dronabinol; marijuana; medical marijuana; nabilone; nabiximols.