Cannabinoid WIN 55,212‐2 induces cell cycle arrest and apoptosis, and inhibits proliferation, migration, invasion, and tumor growth in prostate cancer in a cannabinoid‐receptor 2 dependent manner

Background Cannabinoids have demonstrated anticarcinogenic properties in a variety of malignancies, including in prostate cancer. In the present study, we explored the anti‐cancer effects of the synthetic cannabinoid WIN 55,212‐2 (WIN) in prostate cancer. Methods Established prostate cancer cells (PC3, DU145, LNCaP) were treated with varying concentrations of WIN. Cell proliferation was determined by the MTS assay. The anti‐migration and anti‐invasive potential of WIN was examined by the wound healing assay and the matrigel invasion assay. Cell cycle analysis was performed by flow cytometry, and mechanistic studies were performed by Western blot. Athymic mice ( n = 10) were inoculated with human PC3 cells. Once tumors reached 100 mm 3 , animals were randomized into two groups: saline control and WIN (5 mg/kg), delivered by intraperitoneal injection three times per week for 3 weeks. Results WIN significantly reduced prostate cancer cell proliferation, migration, invasion, induced apoptosis, and arrested cells in Go/G1 phase in a dose‐dependent manner. Mechanistic studies revealed these effects were mediated through a pathway involving cell cycle regulators p27, Cdk4, and pRb. Pre‐treatment with a CB 2 antagonist, AM630, followed by treatment with WIN resulted in a reversal of the anti‐proliferation and cell cycle arrest previously seen with WIN alone. In vivo, administration of WIN resulted in a reduction in the tumor growth rate compared to control ( P < 0.05). Conclusions The following study provides evidence supporting the use of WIN as a novel therapeutic for prostate cancer.