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Breast cancer is the most common cause of cancer deaths in women worldwide. The metastatic spread of breast tumors accounts for the majority of cancer-related deaths and these tumors fail to respond to conventional therapies due to drug resistance and toxicity. In the present study, we investigated the effect of cannabinoids, the active components of Cannabis sativa and their derivatives, on breast cancer growth and metastasis. Cannabinoids have been recently shown to inhibit tumor growth and metastasis in animal models by modulating key cell-signaling pathways. We investigated the effects of synthetic cannabinoids, JWH-133 (CB2 agonist) and WIN-55,212-2 (CB1/CB2 agonist), on breast cancer growth and lung metastasis in vivo. To analyze the effect on breast cancer metastasis, luciferase-positive MDA-MB231-luc-D3H2LN cells were injected intravenously in immunocompromised mice. Metastatic activity was assayed by bioluminescence imaging (BLI) of luciferase transduced cells every week. JWH and WIN (5mg/kg body weight)- treated mice showed a 76% and 67% reduction in lung metastasis respectively, relative to the control group. Also, on gross examination of the lungs at necroscopy, there was a significant reduction of 75% and 67% in lung nodules when mice were treated with JWH and WIN, respectively. Next, to see the effect of JWH and WIN on tumor burden, tumors were induced in immunodeficient mice by subcutaneous flank injection of MDA-MB231 cells. We found that JWH and WIN reduced significantly the growth of the established tumors as compared to control mice. There was a 46% and 42% reduction in tumor volume when the mice were treated with JWH and WIN, respectively. These effects were significantly reversed when CB1 antagonist AM 251 or CB2 antagonist SR144528 were used with WIN and JWH, respectively. Further analysis of molecular mechanisms of cannabinoid-induced inhibitory effects showed a decrease in the expression of COX-2 both at mRNA and protein level in tumors treated with JWH and WIN. The JWH-treated tumors showed an 8 fold decrease whereas WIN-treated tumors showed more than 6 fold decrease of COX-2 levels as compared to the control tumors. Overexpression of COX-2 has been reported in a number of carcinomas and has been associated with uncontrolled cell proliferation. Taken together, these results suggest that cannabinoid receptor agonists have anti-tumor and anti-metastatic potential against breast cancer. Hence these agonists could be used for the treatment of breast cancer growth and metastasis.
Source: AACR Meeting Abstracts | American Association for Cancer Research
Source: AACR Meeting Abstracts | American Association for Cancer Research
