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

Abstract

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 mm3, 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 CB2 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.

Treatment with Cannabinoids as a Promising Approach for Impairing Fibroblast Activation and Prostate Cancer Progression

“…To date, an increasing number of preclinical studies have reported exciting anticancer properties of cannabinoid-related drugs, both in vitro and in xenograft models of several human cancers, including prostate cancer [1][2][3][4][5][6][7][8][9][10][11][12][13]. Interestingly, cannabinoids have been shown to selectively target tumor cells, which upregulate CBs compared with their healthy counterparts.…”

“…In prostate cancer patients, high expression of CB 1 has been associated with a worse prognosis [6,7], and several authors reported CB 1 -mediated anti-proliferative and anti-invasive effects of cannabinoids in prostate cancer cells [8][9][10][11][12]. Furthermore, it has been recently demonstrated that CB 2 also controls tumor cells proliferation, migration, and invasion in both prostate cancer cell lines and in vivo models [13].…”

Cannabinoids and Prostate Cancer: A Systematic Review of Animal Studies

“…The results of the risk of bias [ 49 ] assessment in these studies are presented in Table 1 (individual scores) and Figure 2 . Randomization was only reported in two studies (33.3%) [ 33 , 46 ], but it was unclear whether this occurred in the other studies. Similarly, temperature controls were only reported in two studies (33.3%) [ 33 , 45 ].…”

“…No information was provided regarding attrition bias in these papers. Random group allocation was reported for two studies, but was not clear in the others [ 33 , 46 ]. The blinding of examiners was high in one study, but unclear in the others [ 45 ].…”

“…Furthermore, while a large number of in vitro studies have provided evidence of positive outcomes when using cannabinoids on prostate cancer cells [ 6 , 43 , 44 ], there are relatively very few in vivo studies reported in the literature to date [ 45 , 46 ]. In addition, there are no published clinical studies on cannabis use in prostate cancer, despite extensive experimental in vitro studies highlighting their effectiveness [ 42 , 47 ].…”