title: Pathways mediating the effects of cannabidiol on the reduction of breast cancer cell proliferation, invasion, and metastasis.
abstract: Invasion and metastasis of aggressive breast cancer cells are the final and fatal steps during cancer progression. Clinically, there are still limited therapeutic interventions for aggressive and metastatic breast cancers available. Therefore, effective, targeted, and non-toxic therapies are urgently required. Id-1, an inhibitor of basic helix-loop-helix transcription factors, has recently been shown to be a key regulator of the metastatic potential of breast and additional cancers. We previously reported that cannabidiol (CBD), a cannabinoid with a low toxicity profile, down-regulated Id-1 gene expression in aggressive human breast cancer cells in culture. Using cell proliferation and invasion assays, cell flow cytometry to examine cell cycle and the formation of reactive oxygen species, and Western analysis, we determined pathways leading to the down-regulation of Id-1 expression by CBD and consequently to the inhibition of the proliferative and invasive phenotype of human breast cancer cells. Then, using the mouse 4T1 mammary tumor cell line and the ranksum test, two different syngeneic models of tumor metastasis to the lungs were chosen to determine whether treatment with CBD would reduce metastasis in vivo. We show that CBD inhibits human breast cancer cell proliferation and invasion through differential modulation of the extracellular signal-regulated kinase (ERK) and reactive oxygen species (ROS) pathways, and that both pathways lead to down-regulation of Id-1 expression. Moreover, we demonstrate that CBD up-regulates the pro-differentiation factor, Id-2. Using immune competent mice, we then show that treatment with CBD significantly reduces primary tumor mass as well as the size and number of lung metastatic foci in two models of metastasis. Our data demonstrate the efficacy of CBD in pre-clinical models of breast cancer. The results have the potential to lead to the development of novel non-toxic compounds for the treatment of breast cancer metastasis, and the information gained from these experiments broaden our knowledge of both Id-1 and cannabinoid biology as it pertains to cancer progression.
authors.affiliation: California Pacific Medical Center, Research Institute, San Francisco, CA 94107, USA. mcallis@cpmcri.org
authors.forename: Sean D
authors.initials: SD
authors.lastname: McAllister
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Murase
authors.forename: Rigel T
authors.initials: RT
authors.lastname: Christian
authors.forename: Darryl
authors.initials: D
authors.lastname: Lau
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Zielinski
authors.forename: Juanita
authors.initials: J
authors.lastname: Allison
authors.forename: Carolina
authors.initials: C
authors.lastname: Almanza
authors.forename: Arash
authors.initials: A
authors.lastname: Pakdel
authors.forename: Jasmine
authors.initials: J
authors.lastname: Lee
authors.forename: Chandani
authors.initials: C
authors.lastname: Limbad
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Debs
authors.forename: Dan H
authors.initials: DH
authors.lastname: Moore
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Desprez
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002185:Cannabidiol / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000819:agonists / Q000037:antagonists & inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D014185:Transplantation, Isogeneic; D024502:alpha-Tocopherol / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D002185:Cannabidiol; D048049:Extracellular Signal-Regulated MAP Kinases; D024502:alpha-Tocopherol