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.

Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy

“…Recently, numerous studies have evidenced the role of cannabinoids as potential anti-tumoral drugs owing to their ability to reduce tumor in different animal models, including glioma, 6 breast cancer 7,8 and prostate cancer. 9,10 Recent research has also reported that the synthetic cannabinoid WIN-55 212-2 inhibits HCC growth.…”

A synergistic interaction of 17-β-estradiol with specific cannabinoid receptor type 2 antagonist/inverse agonist on proliferation activity in primary human osteoblasts

“…Notably, it is well-known that long-term use of estrogens can promote carcinogenesis, particularly in breast and endometrial cancer (32)(33)(34). Secondly, a number of studies indicate that the endocannabinoid system plays protective roles against the growth and the spreading of several types of carcinomas, including endometrial and breast cancers (35,36). Therefore, a combination of cannabinoids and estrogens may have beneficial effects by inhibiting estrogen-induced carcinogenesis.…”

Combined Antiproliferative Effects of the Aminoalkylindole WIN55,212-2 and Radiation in Breast Cancer Cells

“…The results of preclinical trials suggest that these agents may prove to be of use for patients experiencing nausea and vomiting due to radiation therapy (Darmani et al, 2007). Cannabinoids are also known to suppress growth or promote cell death in a variety of cancer cell lines, including glioma, pancreatic, melanoma, lymphoma, lung, and breast (Carracedo et al, 2006;Qamri et al, 2009;Salazar et al, 2009;McAllister et al, 2011;Preet et al, 2011;Scuderi et al, 2011;Wasik et al, 2011). Given that cannabinoid-based drugs are used for suppression of nausea and for appetite stimulation in patients with cancer, as well as their potential utility as adjunctive treatments along with conventional therapies such as radiation, the present studies were initiated to determine whether cannabinoids might augment the antiproliferative actions of radiation in breast tumor cells.…”