Inhibition of Breast Cancer Aggressiveness by Cannabidiol

Institution: California Pacific Medical Center Research Institute
Investigator(s): Sean McAllister, Ph.D. -
Award Cycle: 2006 (Cycle 12) Grant #: 12IB-0116 Award: $183,000
Award Type: IDEA
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure

Initial Award Abstract (2006)
An anti-cancer agent with a low toxicity profile that can both inhibit cancer cell growth and metastasis would be extremely valuable clinically. We have discovered that cannabidiol (CBD), a non-psychotropic cannabinoid constituent of the plant Cannabis sativa, can inhibit the growth, migration and invasion of aggressive breast cancer cells in culture. Cannabinoid compounds, in general, have low toxicity profiles. Furthermore, our preliminary research demonstrated that CBD is a novel inhibitor of a protein whose activity has been closely linked to the aggressiveness of human breast cancers; called inhibitor of DNA binding-1 (Id-1). Whether CBD can inhibit the spread of metastatic breast cancer in vivo (in the body), compared to cell culture conditions, has not been determined. However, CBD has been demonstrated to inhibit aggressive human brain cancers in vivo. Understanding the mechanisms behind the anti-cancer activity of CBD may lead to the validation of new biological targets for diagnostics and therapies for breast cancer.

To study the effects of CBD on the growth and spread of aggressive breast cancer, we will use time lapse microscopy to capture detailed changes in cell growth/death, migration, and morphology. Classical biochemical measures of cell growth/death and invasion will also be used in combination with novel compounds to identify receptors that CBD interacts with to produce its anti- breast cancer effects. A mouse model of breast cancer metastasis will be used to determine whether CBD effectively reduces the spread of aggressive breast cancer in vivo. At the intracellular level, we will study whether CBD, (1) regulates Id-1 in an extracellular signal-regulated kinase-dependent manner, and (2) serves to activate a pro-apoptotic (cell death) pathway in a caspase-dependent manner.

Novel and effective non-toxic therapies for aggressive breast cancers are urgently required. Plant cannabinoids are compounds that are well tolerated during chronic (long-term) administration. CBD, and compounds based on its structure, may be the basis for the treatment of metastatic breast cancer. If successful, our studies will set the stage for additional translational work to develop CBDs eligibility for clinical trials.

Final Report (2008)
We discovered that cannabidiol (CBD), a non-psychotropic compound from the plant Cannabis sativa, can inhibit the process of breast cancer cells that allow them to grow and spread (metastasis). CBD can also inhibit breast cancer metastasis in a mouse model. The research carried out in our CBCRP proposal demonstrated that CBD is a novel inhibitor of a gene whose activity is intimately linked to the aggressiveness of human breast cancers; this gene has been termed Id-1. Notably, our findings also indicated that Id-1 was a key gene whose expression needed to be reduced in order for CBD to inhibit aggressive breast cancer. One of the most significant high risk components of the initial application was to determine if CBD had appreciable efficacy against breast cancer in vivo (i.e., animal models). This high risk component was not pursued, since an independent group showed CBD was able to inhibit metastasis of MDA-MB231 cells to the lung of nude mice. Building of the previous findings, we made small structural changes to CBD that are expected to produce drugs that are much more active than CBD at inhibiting Id-1 and corresponding aggressive breast cancers. CBD has a low toxicity profile. An anticancer agent with a low toxicity profile that can both inhibit cancer cell growth and metastasis would be extremely valuable clinically. Understanding the mechanisms behind the anticancer activity of CBD may also lead to the discovery of new biological targets for the development of diagnostic tools and additional therapies for the treatment of cancer. In this project we found portions of the CBD structure essential to its biological activity for breast cancer cell growth inhibition. We are in the process of filing a patent on these discoveries. In addition, we studies the moleculr mechanisms that underlie CBD activity, and found that sustained upregulation of Erk (extracellular signal-regulated kinases, a type of protein kinase intracellular signaling molecules) is key to the ability of CBD to regulate the metastasis-specific inhibition of the Id-1 transcription factor.

Symposium Abstract (2007)
The spread (metastasis) of aggressive breast cancer cells to other parts of the body is the final and fatal step during cancer progression. Clinically, there are still limited therapeutic interventions for aggressive breast cancers available. Clearly, effective and non-toxic therapies are urgently required. The Id-1 gene, a helix-loop-helix type transcription factor, has recently been shown to be a key regulator of the metastatic potential of breast and additional cancers. We previously determined that aggressive breast cancer cells became significantly less invasive in vitro (in culture) and less metastatic in vivo (in mice) when Id-1 expression was reduced using a technique called gene antisense therapy. It is not possible at this point, however, to use this technology to reduce Id-1 expression in patients with metastatic breast cancer.

In our search for a non-toxic drug that could inhibit Id-1 expression, a potential candidate agent was discovered. Here we report that cannabidiol (CBD), a compound extracted from cannabis and with a low toxicity profile, can down-regulate Id-1 expression in aggressive human breast cancer cells. The CBD concentrations effective at inhibiting Id-1 expression correlated with those used to inhibit the proliferative and invasive characteristics of aggressive breast cancer cells. CBD was able to inhibit Id-1 expression at the mRNA and protein level in a concentration-dependent fashion. Most importantly, constitutive expression of Id-1 in breast cancer cells abolished the effects of CBD on cell invasiveness. This suggests that Id-1 is indeed a key factor whose expression needs to be down-regulated in order to observe the effects of CBD on the reduction of breast cancer cell aggressiveness. In conclusion, CBD represents the first non-toxic drug that can significantly decrease Id-1 expression in metastatic breast cancer cells leading to reduction of tumor aggressiveness.

CBD and additional analogs based off its structure could be used as inhibitors of Id-1 and might be of benefit for patients with breast cancers. Cannabinoids are already being used in clinical trials for purposes unrelated to their anticancer activity and these compounds have been reported to be well tolerated. We expect that using CBD as a template will lead to the discovery of more potent and efficacious drugs. This research could lead to a new area of investigation in the treatment of aggressive forms of breast cancer with novel cannabinoid compounds.

Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells.
Periodical:Molecular Cancer Therapeutics
Index Medicus: Mol Cancer Ther
Authors: McAllister SD, Christian RT, Horowitz MP, Garcia A, Desprez PY.
Yr: 2007 Vol: 6 Nbr: 11 Abs: Pg:2921-7