Now showing 1 - 1 of 1
  • Publication
    Investigating chemopreventive and chemotherapeutic applications of cannabinoids in prostate cancer
    (University College Dublin. School of Biology and Environmental Science, 2022) ;
    0000-0001-8301-5846
    Prostate cancer is the 5th leading cause of cancer death in men, responsible for more than 375,000 deaths worldwide in 2020. For patients with localised prostate cancer, the 5-year survival rate is close to 100%. However, metastatic prostate cancer remains a lethal disease, with a 5-year survival rate of just 30%. Therefore, novel therapeutic strategies are urgently needed to improve clinical outcomes for patients with advanced prostate cancer. Cannabinoids, chemical components of the cannabis plant, pose a possible solution. Substantial preclinical evidence demonstrates that cannabinoids can modulate key hallmarks of cancer, including cell death, proliferation, migration and invasion, and angiogenesis. However, few studies have investigated the anti-cancer potential of cannabinoids in prostate cancer. Our overall hypothesis was that plant-derived cannabinoids (phytocannabinoids) have chemotherapeutic and chemopreventive effects in prostate cancer. To test this hypothesis, our specific aims were to assess the effects of cannabinoids on various hallmarks of cancer, to investigate the mechanisms underlying the observed phenotypic effects, and to determine whether phytocannabinoids have antioxidant or chemopreventive effects in non-cancerous prostate cells. First, we used cell line models of prostate cancer to measure the effects of cannabinoid treatment on cell viability, survival, proliferation, apoptosis, and migration and invasion. The non-psychoactive phytocannabinoid GL1a inhibited prostate cancer cell viability and proliferation, with no significant increase in apoptosis. GL1a reduced the invasiveness of highly metastatic PC-3 cells. We also found some evidence that combinations of cannabinoid compounds produce enhanced anti-cancer activity. However, GL1a also reduced viability and induced apoptosis in non-cancerous prostate cells and further investigation into possible off-target effects is warranted. Having shown that GL1a reduced cell proliferation and invasion, our next goal was to investigate the underlying mechanisms. Specifically, we aimed to identify the receptor targets of GL1a in prostate cancer cells and to measure the effects of GL1a treatment on the expression of cell cycle proteins, the phosphorylation of protein kinases, and the expression and secretion of proteins involved in cell invasion. GL1a reduced the expression of the key cell cycle proteins cyclin D3, CDK2, CDK4, and CDK1, and reduced the phosphorylation and activation of the protein kinase AKT. Additionally, we found some evidence that GL1a may increase the expression of E-cadherin, an adhesion protein associated with a non-invasive phenotype. The effects of GL1a on cell viability were not blocked by CB1 or CB2 antagonists, TRPV ion channel blockers, or a GPR55 agonist, suggesting that GL1a acts independently of these targets in prostate cancer cells. Finally, we assessed the antioxidant and cytoprotective potential of low-dose cannabinoids in non-cancerous prostate cells. Hydrogen peroxide was used to induce oxidative stress. Phytocannabinoid treatment at the doses tested produced no significant cytoprotective or antioxidant effects. However, drug exposure times and doses may require further optimisation. This study provides novel insights into the phenotypic effects and mechanisms of action of cannabinoids in prostate cancer cells. GL1a reduces prostate cancer cell proliferation and invasion. The underlying mechanisms include altered expression of key cell cycle regulators and modulation of AKT phosphorylation. Future studies should aim to identify the receptor target(s) of GL1a and further investigate its mechanisms of action, as well as testing the effects of cannabinoid treatment in more biologically relevant experimental models. Ultimately, clinical trials will be needed to determine whether the observed phenotypic effects of GL1a in vitro can translate to therapeutic benefits and improved outcomes in patients with prostate cancer.
      49