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Synthetic cannabinoid receptor agonists inhibit tumor growth and metastasis of breast cancer.

Abstract

Cannabinoids have been reported to possess antitumorogenic activity. Not much is known, however, about the effects and mechanism of action of synthetic nonpsychotic cannabinoids on breast cancer growth and metastasis. We have shown that the cannabinoid receptors CB1 and CB2 are overexpressed in primary human breast tumors compared with normal breast tissue. We have also observed that the breast cancer cell lines MDA-MB231, MDA-MB231-luc, and MDA-MB468 express CB1 and CB2 receptors. Furthermore, we have shown that the CB2 synthetic agonist JWH-133 and the CB1 and CB2 agonist WIN-55,212-2 inhibit cell proliferation and migration under in vitro conditions. These results were confirmed in vivo in various mouse model systems. Mice treated with JWH-133 or WIN-55,212-2 showed a 40% to 50% reduction in tumor growth and a 65% to 80% reduction in lung metastasis. These effects were reversed by CB1 and CB2 antagonists AM 251 and SR144528, respectively, suggesting involvement of CB1 and CB2 receptors. In addition, the CB2 agonist JWH-133 was shown to delay and reduce mammary gland tumors in the polyoma middle T oncoprotein (PyMT) transgenic mouse model system. Upon further elucidation, we observed that JWH-133 and WIN-55,212-2 mediate the breast tumor-suppressive effects via a coordinated regulation of cyclooxygenase-2/prostaglandin E2 signaling pathways and induction of apoptosis. These results indicate that CB1 and CB2 receptors could be used to develop novel therapeutic strategies against breast cancer growth and metastasis.

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  • Authors+Show Affiliations

    ,

    Department of Pathology, Ohio State University Medical Center, Columbus, OH 43210, USA.

    , , , , ,

    Source

    Molecular cancer therapeutics 8:11 2009 Nov pg 3117-29

    MeSH

    Animals
    Apoptosis
    Benzoxazines
    Breast Neoplasms
    Cannabinoids
    Cell Cycle
    Cell Growth Processes
    Cell Line, Tumor
    Cell Movement
    Cyclooxygenase 2
    Dinoprostone
    Female
    Humans
    Immunohistochemistry
    Lung Neoplasms
    Male
    Mammary Neoplasms, Experimental
    Mice
    Mice, Inbred C3H
    Mice, SCID
    Mice, Transgenic
    Microscopy, Confocal
    Morpholines
    Naphthalenes
    Neoplasm Metastasis
    Neovascularization, Pathologic
    RNA, Small Interfering
    Receptor, Cannabinoid, CB1
    Receptor, Cannabinoid, CB2
    Signal Transduction
    Transfection
    Xenograft Model Antitumor Assays

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    19887554

    Citation

    Qamri, Zahida, et al. "Synthetic Cannabinoid Receptor Agonists Inhibit Tumor Growth and Metastasis of Breast Cancer." Molecular Cancer Therapeutics, vol. 8, no. 11, 2009, pp. 3117-29.
    Qamri Z, Preet A, Nasser MW, et al. Synthetic cannabinoid receptor agonists inhibit tumor growth and metastasis of breast cancer. Mol Cancer Ther. 2009;8(11):3117-29.
    Qamri, Z., Preet, A., Nasser, M. W., Bass, C. E., Leone, G., Barsky, S. H., & Ganju, R. K. (2009). Synthetic cannabinoid receptor agonists inhibit tumor growth and metastasis of breast cancer. Molecular Cancer Therapeutics, 8(11), pp. 3117-29. doi:10.1158/1535-7163.MCT-09-0448.
    Qamri Z, et al. Synthetic Cannabinoid Receptor Agonists Inhibit Tumor Growth and Metastasis of Breast Cancer. Mol Cancer Ther. 2009;8(11):3117-29. PubMed PMID: 19887554.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Synthetic cannabinoid receptor agonists inhibit tumor growth and metastasis of breast cancer. AU - Qamri,Zahida, AU - Preet,Anju, AU - Nasser,Mohd W, AU - Bass,Caroline E, AU - Leone,Gustavo, AU - Barsky,Sanford H, AU - Ganju,Ramesh K, Y1 - 2009/11/03/ PY - 2009/11/6/entrez PY - 2009/11/6/pubmed PY - 2010/5/28/medline SP - 3117 EP - 29 JF - Molecular cancer therapeutics JO - Mol. Cancer Ther. VL - 8 IS - 11 N2 - Cannabinoids have been reported to possess antitumorogenic activity. Not much is known, however, about the effects and mechanism of action of synthetic nonpsychotic cannabinoids on breast cancer growth and metastasis. We have shown that the cannabinoid receptors CB1 and CB2 are overexpressed in primary human breast tumors compared with normal breast tissue. We have also observed that the breast cancer cell lines MDA-MB231, MDA-MB231-luc, and MDA-MB468 express CB1 and CB2 receptors. Furthermore, we have shown that the CB2 synthetic agonist JWH-133 and the CB1 and CB2 agonist WIN-55,212-2 inhibit cell proliferation and migration under in vitro conditions. These results were confirmed in vivo in various mouse model systems. Mice treated with JWH-133 or WIN-55,212-2 showed a 40% to 50% reduction in tumor growth and a 65% to 80% reduction in lung metastasis. These effects were reversed by CB1 and CB2 antagonists AM 251 and SR144528, respectively, suggesting involvement of CB1 and CB2 receptors. In addition, the CB2 agonist JWH-133 was shown to delay and reduce mammary gland tumors in the polyoma middle T oncoprotein (PyMT) transgenic mouse model system. Upon further elucidation, we observed that JWH-133 and WIN-55,212-2 mediate the breast tumor-suppressive effects via a coordinated regulation of cyclooxygenase-2/prostaglandin E2 signaling pathways and induction of apoptosis. These results indicate that CB1 and CB2 receptors could be used to develop novel therapeutic strategies against breast cancer growth and metastasis. SN - 1538-8514 UR - https://www.unboundmedicine.com/medline/citation/19887554/Synthetic_cannabinoid_receptor_agonists_inhibit_tumor_growth_and_metastasis_of_breast_cancer_ L2 - http://mct.aacrjournals.org/cgi/pmidlookup?view=long&pmid=19887554 DB - PRIME DP - Unbound Medicine ER -