Proapoptotic effect of endocannabinoids in prostate cancer cells

Abstract

In the early stages, prostate cancer is androgen- dependent; therefore, medical castration has shown significant results during the initial stages of this pathology. Despite this early effect, advanced prostate cancer is resilient to such treatment. Recent evidence shows that derivatives of Cannabis sativa and its analogs may exert a protective effect against different types of oncologic pathologies. The purpose of the present study was to detect the presence of cannabinoid receptors (CB1 and CB2) on cancer cells with a prostatic origin and to evaluate the effect of the in vitro use of synthetic analogs. In order to do this, we used a commercial cell line and primary cultures derived from prostate cancer and benign prostatic hyperplasia. The presence of the CB1 and CB2 receptors was determined by immunohistochemistry where we showed a higher expression of these receptors in later stages of the disease (samples with a high Gleason score). Later, treatments were conducted using anandamide, 2-arachidonoyl glycerol and a synthetic analog of anandamide, methanandamide. Using the MTT assay, we proved that the treatments produced a cell growth inhibitory effect on all the different prostate cancer cultures. This effect was demonstrated to be dose-dependent. The use of a specific CB1 receptor blocker (SR141716) confirmed that this effect was produced primarily from the activation of the CB1 receptor. In order to understand the MTT assay results, we determined cell cycle distribution by flow cytometry, which showed no variation at the different cell cycle stages in all the cultures after treatment. Treatment with endocannabinoids resulted in an increase in the percentage of apoptotic cells as determined by Annexin V assays and caused an increase in the levels of activated caspase-3 and a reduction in the levels of Bcl-2 confirming that the reduction in cell viability noted in the MTT assay was caused by the activation of the apoptotic pathway. Finally, we observed that endocannabinoid treatment activated the Erk pathway and at the same time, produced a decrease in the activation levels of the Akt pathway. Based on these results, we suggest that endocannabinoids may be a beneficial option for the treatment of prostate cancer that has become nonresponsive to common therapies.

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

“…Several studies have demonstrated the anti-proliferative and proapoptotic effect of a variety of cannabinoids in prostate cancer, including the endocannabinoids anandamide and 2-arachidonoyl glycerol, and phytocannabinoids cannabidiol and tetrahydrocannabinol. 5,[17][18][19] We have shown that treatment with the synthetic cannabinoid WIN significantly inhibits cell proliferation and induces apoptosis in human prostate cancer cells in a dose-dependent manner (Figures 1, 3A, and 3B, respectively).…”

Insights into the effects of the endocannabinoid system in cancer: a review

“…In prostate carcinomas, expressions of both CB 1 and CB 2 receptors were increased compared to the normal prostatic tissue (Orellana‐Serradell et al, ), and the overexpression of CB 1 receptors has been associated with a higher Gleason score and metastasis incidence, being a negative marker of disease outcome. (Chung et al, ; Cipriano et al, ).…”

Effect of endocannabinoid signalling on cell fate: life, death, differentiation and proliferation of brain cells

“…Similarly, activation of either CB 1 or CB 2 receptors with THC was demonstrated to induce an inhibitory effect on ERK and Akt in human Jurkat leukaemia T cells (Jia et al, ). However, in prostate cancer cells, the apoptosis induced by eCBs (either AEA or 2‐AG) acting on CB 1 receptors was found to be the result of an inhibitory effect on the Akt pathway whereas the ERK signalling cascade was activated (Orellana‐Serradell et al, ).…”