Basic Science Researcher - California Pacific Medical Center Research Institute
Sean D. McAllister, PhD
Our research team is studying the potential of the endocannabinoid system to control cell fate with the goal of developing therapeutic interventions for aggressive cancers. This newly discovered biological system can be regulated by many different classes of cannabinoid compounds that work through specific cellular receptors. The cloned cannabinoid receptors have been termed cannabinoid 1 (CB1) and (CB2).
Δ9-tetrahydrocannabinol (THC), a mixed CB1 and CB2 receptor agonist, is the primary active constituent of Cannabis sativa and is currently being used in a clinical trial for the treatment of aggressive recurrent glioblastoma multiforme (GBM). Cannabinoids are also being used in clinical trials for purposes unrelated to their direct anticancer activity. The compounds have been reported to be well tolerated during chronic oral and systemic administration. In addition to Δ9-THC, cannabidiol (CBD), cannabinol (CBN) and cannabigerol (CBG) are also present in reasonable quantities in Cannabis. CBN has low affinity for CB1 and CB2 receptors, whereas the non-psychotropic cannabinoids, CBD and CBG, have negligible affinity for the cloned receptors. We have determined that these additional cannabinoids are also effective and inhibiting aggressive cancers. Importantly, we have discovered in vitro that a synergistic increase in the antiproliferative and apoptotic activity of cannabinoids can be produced by combining specific ratios of CB1 and CB2 receptors agonists with non-psychotropic cannabinoids.
We are currently determining the molecular mechanism that may explain the synergistic increase in anticancer activity that is observed with the combination treatments. We are also studying whether this combination strategy will lead to greater antitumor activity in vivo.
In addition to the combination therapy project, we are working in collaboration with Dr. Pierre Desprez to develop novel inhibitors of Id-1 using cannabinoid compounds. Id-1 is a helix-loop-helix protein that acts as an inhibitor of basic helix-loop-helix transcription factors that control cell differentiation, development and carcinogenesis. Past research of Id-1 expression in normal and cancerous breast cells, as well as in mouse mammary glands and in human breast cancer biopsies, demonstrated that increased Id-1 expression was associated with a proliferative and invasive phenotype. Specifically, it was found that Id-1 was constitutively expressed at a high level in aggressive breast cancer cells and human biopsies, and that aggressiveness was reverted in vitro and in vivo when Id-1 expression was targeted using antisense technology. Importantly, we have recently discovered that CBD, a nontoxic cannabinoid that lacks psychoactivity, can inhibit Id-1 gene expression in metastatic breast cancer cells and consequently their aggressive phenotype. The down-regulation of expression was the result of the inhibition of the endogenous Id-1 promoter and corresponding mRNA and protein levels. CBD and compounds based off of its structure can therefore potentially be used as therapeutic agents. CBD also inhibits breast cancer metastasis in vivo.
Based off of our recent findings, we are currently involved in 1) developing novel CBD analogs for the treat of aggressive breast cancers 2) discovering the detailed mechanisms through which cannabinoid compounds regulate Id-1 expression.
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Publications by Sean D. McAllister, PhD in PubMed.
Representative publications include:
- McAllister, S.D., Christian, R.T., Lau, D., Zielinski, A., Allison, J., Almanza, C., Pakdel, A., Lee, J., Moore, D.H., and Desprez, P.Y. (2010). Pathways Mediating the Effects of Cannabidiol on the Reduction of Breast Cancer Cell Proliferation, Invasion and Metastasis. Breast Cancer Research and Treatment. Sep 22. [Epub ahead of print]
- Marcu, J.P., Christian, R.T., Lau, D., Zielinski, A.J., Horowitz, M.P., Lee, J., Pakdel, A., Limbad, C., Moore, D.H., Yount, G.L., Desprez, P.Y. and McAllister, S.D. (2010) Cannabidiol enhances the inhibitory effects of D9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival. Molecular Cancer Therapeutics. Jan;9(1):180-9.
- McAllister, S.D., Christian, R.T., Horowitz, M.P., Garcia, A. and Desprez. P (2007). Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells. Molecular Cancer Therapeutics 6 (11): 2921-2927, November 1, 2007
- McAllister, S.D., Chan, C., Taft, R.J., Luu, T., Abood, M.E., Moore, D.H., Aldape, K., Yount, G. (2005) Cannabinoids selectively inhibit proliferation and induce death of cultured human glioblastoma multiforme cells. Journal of Neuro-Oncology (74):31-40
- McAllister, S.D. and Abood, M.E. (2005) Endocannabinoids and intracellular signalling. In Endocannabinoids: The Brain and Body’s Marijuana and Beyond. Ed: Onaivi, E. Taylor and Francis Books, New Fetter Lane, London.
- McAllister, S.D., Hurst, D.P., Barnett-Norris, J., Lynch, D., Reggio, P.H., and Abood, M.E. (2004) Structural mimicry in class A GPCR rotamer toggle switches: the importance of the F3.36(201)/W6.48(357) interaction in cannabinoid CB1 receptor activation. Journal of Biological Chemistry Nov 12;279(46):48024-37
- McAllister, S.D., Rizvi G., Hurst, D.P., Barnett-Norris, J., Lynch, D., Reggio, P.H., Abood, M.E. (2003) An Aromatic Microdomain at the Cannabinoid CB1 Receptor Constitutes an Agonist/Inverse Agonist Binding Region. Journal of Medicinal Chemistry. Nov 20; 46(24): 5139-52.
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Recent research on cannabidiol inhibiting breast cancer and clinical trials with cannabinoids