“Introduction: Cannabis sativa extract has been used as an herbal medicine since ancient times. It is one of the most researched extracts, especially among supportive treatments against cancer. Prostate cancer is one of the most frequently diagnosed cancer types in men worldwide and an estimated 288,300 new cases were diagnosed in 2023. Today, many advanced therapeutic approaches are used for prostate cancer, such as immunotherapy and chemotherapy, but acquired drug resistance, long-term drug usage and differentiation of cancer cells mostly restricted the efficiency of therapies. Therefore, it is thought that the use of natural products to overcome these limitations and improve the effectiveness of existing therapies may offer promising approaches. The present study focused on the investigation of the possible enhancer role of cannabidiol (CBD), which is a potent ingredient compound of Cannabis, on the chemotherapeutic agent etoposide in prostate cancer cells. 

Methods: Herein, we tested the potentiator role of CBD on etoposide in prostate cancer cells by testing the cytotoxic effect, morphological alterations, apoptotic effects, autophagy, unfolded protein response (UPR) signaling, endoplasmic reticulum-associated degradation mechanism (ERAD), angiogenic and androgenic factors, and epithelial-mesenchymal transition (EMT). In addition, we examined the combined treatment of CBD and etoposide on colonial growth, migrative, invasive capability, 3D tumor formation, and cellular senescence. 

Results: Our findings demonstrated that cotreatment of etoposide with CBD importantly suppressed autophagic flux and induced ERAD and UPR signaling in LNCaP cells. Also, CBD strongly enhanced the etoposide-mediated suppression of androgenic signaling, angiogenic factor VEGF-A, protooncogene c-Myc, EMT, and also induced apoptosis through activation caspase-3 and PARP-1. Moreover, coadministration markedly decreased tumorigenic properties, such as proliferative capacity, colonial growth, migration, and 3D tumor formation and also induced senescence. Altogether, our data revealed that CBD has a potent enhancer effect on etoposide-associated anticancer activities. 

Conclusion: The present study suggests that the use of CBD as a supportive therapy in existing chemotherapeutic approaches may be a promising option, but this effectiveness needs to be investigated on a large scale.”

https://pubmed.ncbi.nlm.nih.gov/39161998/

https://www.liebertpub.com/doi/10.1089/can.2023.0284

“Prostate cancer is the second most frequent cancer diagnosed in men in the world today. Almost all prostate cancers are adenocarcinomas and develop from gland cells. We used the PC3 prostate cancer cell line, which is well studied and derived from a bone metastasis of a grade IV prostatic adenocarcinoma.

Cannabidiol (CBD), a major non-psychoactive constituent of cannabis, is a cannabinoid with anti-tumor properties but its effects on prostate cancer cells are not studied in detail.

Here, we found cannabidiol decreased prostate cancer cell (PC3) viability up to 37.25% and induced apoptotic cell death in a time and dose-dependent manner. We found that CBD activated the caspases 3/7 pathways and increased DNA fragmentation. Furthermore, we observed an increase of pro-apoptotic genes Bax, an increased level of reactive oxygen species, lower reduced glutathione level, and altered mitochondrial potential in response to CBD treatment leading to lower cellular ATP.

Overall, our results suggest that CBD may be effective against prostate cancer cells.”

https://pubmed.ncbi.nlm.nih.gov/37796968/

“In summary, we have demonstrated CBD as a potential therapeutic molecule in the treatment of prostate cancer based on its properties of anti-proliferative effect on PC3 cancer cells by promoting intrinsic apoptotic pathway via mitochondrial and NFkB activation followed by intracellular ROS generation and reducing cellular redox status of glutathione.”

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0286758

“Prostate cancer is the fifth leading cause of cancer death in men, responsible for over 375,000 deaths in 2020. Novel therapeutic strategies are needed to improve outcomes. Cannabinoids, chemical components of the cannabis plant, are a possible solution.

Preclinical evidence demonstrates that cannabinoids can modulate several cancer hallmarks of many tumor types. However, the therapeutic potential of cannabinoids in prostate cancer has not yet been fully explored. The aim of this study was to investigate the antiproliferative and anti-invasive properties of cannabidiol (CBD) in prostate cancer cells in vitro.

CBD inhibited cell viability and proliferation, accompanied by reduced expression of key cell cycle proteins, specifically cyclin D3 and cyclin-dependent kinases CDK2, CDK4, and CDK1, and inhibition of AKT phosphorylation. The effects of CBD on cell viability were not blocked by cannabinoid receptor antagonists, a transient receptor potential vanilloid 1 (TRPV1) channel blocker, or an agonist of the G-protein-coupled receptor GPR55, suggesting that CBD acts independently of these targets in prostate cancer cells. Furthermore, CBD reduced the invasiveness of highly metastatic PC-3 cells and increased protein expression of E-cadherin.

The ability of CBD to inhibit prostate cancer cell proliferation and invasiveness suggests that CBD may have potential as a future chemotherapeutic agent.”

https://pubmed.ncbi.nlm.nih.gov/37703852/

“These findings suggest that CBD has potential as a future chemotherapeutic agent for prostate cancer.”

https://pubs.acs.org/doi/10.1021/acs.jnatprod.3c00363

“Purpose: Cannabinoids (CBD) have anti-tumor activity against prostate cancer (PCa). Preclinical studies have demonstrated a significant decrease in prostate specific antigen (PSA) protein expression and reduced tumor growth in xenografts of LNCaP and DU-145 cells in athymic mice when treated with CBD. Over-the-counter CBD products may vary in activity without clear standardization, and Epidiolex is a standardized FDA-approved oral CBD solution for treatment of certain types of seizures. We aimed to assess the safety and preliminary anti-tumor activity of Epidiolex in patients with biochemically recurrent (BCR) PCa.

Experimental design: This was an open-label, single center, phase I dose escalation study followed by a dose expansion in BCR patients after primary definitive local therapy (prostatectomy +/- salvage radiotherapy or primary definitive radiotherapy). Eligible patients were screened for urine tetrahydrocannabinol prior to enrollment. The starting dose level of Epidiolex was 600 mg by mouth once daily and escalated to 800 mg daily with the use of a Bayesian optimal interval design. All patients were treated for 90 days followed by a 10-day taper. The primary endpoints were safety and tolerability. Changes in PSA, testosterone levels, and patient-reported health-related quality of life were studied as secondary endpoints.

Results: Seven patients were enrolled into the dose escalation cohort. There were no dose-limiting toxicities at the first two dose levels (600 mg and 800 mg). An additional 14 patients were enrolled at the 800 mg dose level into the dose expansion cohort. The most common adverse events were 55% diarrhea (grade 1-2), 25% nausea (grade 1-2), and 20% fatigue (grade 1-2). The mean PSA at baseline was 2.9 ng/mL. At the 12-week landmark time-point, 16 out of 18 (88%) had stable biochemical disease, one (5%) had partial biochemical response with the greatest measurable decline being 41%, and one (5%) had PSA progression. No statistically significant changes were observed in patient-reported outcomes (PROs), but PROs changed in the direction of supporting the tolerability of Epidiolex (e.g., emotional functioning improved).

Conclusion: Epidiolex at a dose of 800 mg daily appears to be safe and tolerable in patients with BCR prostate cancer supporting a safe dose for future studies.”

https://pubmed.ncbi.nlm.nih.gov/37173971/

“Cannabinoids have been widely used for pain, nausea, and appetite stimulation, and have also shown anti-tumor activity in preclinical studies of prostate cancer. Epidiolex is an oral cannabidiol solution that is FDA approved for the treatment of certain types of seizures in patients one year of age and older. We studied phase I Epidiolex dose escalation followed by dose expansion in patients with biochemically recurrent prostate cancer. A total of 21 patients were enrolled. No dose-limiting toxicities were observed at any dose level. The recommended phase 2 dose was 800 mg daily. An additional 14 patients were enrolled in the dose expansion. The most common adverse events were 55% diarrhea (grade 1–2), 25% nausea (grade 1–2), and 20% fatigue (grade 1–2). Epidiolex at a dose of 800 mg daily appears to be safe and tolerable in patients with BCR prostate cancer, supporting a safe dose for future studies.”

https://www.mdpi.com/2072-6694/15/9/2505

“Background: Prostate cancer is the second most frequently occurring carcinoma in males worldwide and one of the leading causes of death in men around the world. Recent studies estimate that over 1.4 million males are diagnosed with prostate cancer on an annual basis, with approximately 375,000 succumbing to the disease annually. With current treatments continuing to show severe side effects, there is a need for new treatments. In this study we looked at the effect of cannabis sativa extract, cannabidiol and cisplatin on prostate cancer cells, PC3.

Methods: In addressing the above questions, we employed the MTT assay to measure the antiproliferative effect on PC3 cells following treatment with varying concentrations of Cannabis sativa extract, cisplatin and cannabidiol. xCELLigence was also used to confirm the IC50 activity in which cells were grown in a 16 well plate coated with gold and monitor cell attachment. Caspase 3/7 activity was also measured using 96 well-plate following treatment. Western-blot and qRT-PCR was also used to measure the gene expression of tumour suppressor genes, p53, Bax and Bcl2. Animal studies were employed to measure the growth of PC3-mouse derived cancer to evaluate the effect of compounds in vivo.

Results: From the treatment with varying concentrations of Cannabis sativa extract, cannabidiol and cisplatin, we have observed that the three compounds induced antiproliferation of PC3 cancer cell lines through the activation of caspase 3/7 activity. We also observed induction of apoptosis in these cells following silencing of retinoblastoma binding protein 6 (RBBP6), with upregulation of p53 and bax mRNA expression, and a reduction in Bcl2 gene expression. The growth of tumours in the mouse models were reduced following treatment with cisplatin and cannabidiol.

Conclusion: We demonstrated that cannabidiol is a viable therapy to treat prostate cancer cells, in combination with silencing of RBBP6. This suggests that cannabidiol rather Cannabis sativa extract may play an important role in reducing cancer progression.”

https://pubmed.ncbi.nlm.nih.gov/36853473/

“In conclusion, these results further suggest that CBD is an effective anti-tumor drug which possesses anti-proliferative and pro-apoptotic properties. Additionally, these findings point to a crosstalk between RBBP6 silencing and CBD treatment rather than Cannabis sativa extract. Moreover, CBD-siRBBP6 has shown an important role of p53 up-regulation in prostate cancer, a tumor microenvironment modulating property. In conclusion, the findings of this study promote using CBD in cancer patients mostly with an inactivated p53 gene.”

https://link.springer.com/article/10.1007/s11033-022-08197-0