Synthetic and Endogenous Cannabinoids Inhibit Breast Cancer Cell Growth and Metastasis
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Publisher:The Ohio State University
Series/Report no.:The Ohio State University. Department of Biochemistry Honors Theses; 2011
With one million cases diagnosed yearly worldwide, breast cancer is the second most common cancer in women. Metastasis to the brain is the leading cause of death in breast cancer patients due to the inability of drug treatments to cross the blood brain barrier, limiting the efficacy of some forms of chemotherapy. The most common chemokine receptor expressed by breast cancer cells is CXCR4, a protein involved in cell migration. CXCR4’s ligand Stromal Derived Factor 1 (SDF1-a or CXCL12) is expressed by the tissues to which breast cancer migrates, suggesting that the CXCR4/CXCL12 axis plays a role in metastasis of breast cancer cells to the brain. Endogenously produced endocannabinoids 2- arachidonoylglycerol (2-AG) and anandamide (AEA), and synthetic cannabinoids JWH- 015 and Met-F-AEA bind to cannabinoid receptors CB1 and CB2. Cannabinoid receptor inhibition by synthetic cannabinoids has been shown to block CXCR4/CXCL12-mediated in vitro migration of immune cells. Due to the high expression of CB1 receptor in the brain, cannabinoids have the ability to cross the blood brain barrier, implicating their capacity to inhibit breast cancer cell metastasis to the brain. Therefore, we explored the ability of endogenous and synthetic cannabinoids to inhibit CXCR4/CXCL12-induced in vitro metastatic assays using various breast cancer cell lines such as MDA-MB-231/BR3 (that specifically metastasizes to the brain), NT2.5 (highly metastatic mouse breast cancer cell line), MCF7-CXCR4 (highly expresses CXCR4), and SCP2 (highly metastatic human cell line). These cell lines were used to perform various CXCL12-induced invasive assays such as wound healing, chemotaxis, and chemoinvasion in the presence of endogenous and synthetic cannabinoids. These cannabinoids significantly reduced breast cancer cell chemoinvasion, migration and wound healing. Furthermore, delineation of signaling mechanisms revealed that cannabinoids may inhibit chemoinvasive properties of breast cancer cells by inhibiting CXCL12-induced ERK activity and focal adhesion kinase complex formation. These studies suggest that cannabinoids have the potential to inhibit metastasis of breast cancer cells to various organs including the brain. With future in vivo studies using various animal models, including knock-out mouse models which address dosage/targeting issues, endogenous and synthetic cannabinoids could be used to develop new therapies for breast cancer growth and metastasis.
Research funded by Undergraduate Research Office, College of Pharmacy Department of Pathology, and College of Arts and Sciences
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