Cannabinoids in Treating Chemotherapy-Induced Nausea and Vomiting, Cancer-Associated Pain, and Tumor Growth

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“Cannabis has been used as an herbal remedy for thousands of years, and recent research indicates promising new uses in medicine. So far, some studies have shown cannabinoids to be safe in helping mitigate some cancer-associated complications, including chemotherapy-induced nausea and vomiting, cancer-associated pain, and tumor growth.

Researchers have been particularly interested in the potential uses of cannabinoids in treating cancer due to their ability to regulate cancer-related cell cycle pathways, prompting many beneficial effects, such as tumor growth prevention, cell cycle obstruction, and cell death.

Cannabinoids have been found to affect tumors of the brain, prostate, colon and rectum, breast, uterus, cervix, thyroid, skin, pancreas, and lymph. However, the full potential of cannabinoids is yet to be understood.

This review discusses current knowledge on the promising applications of cannabinoids in treating three different side effects of cancer-chemotherapy-induced nausea and vomiting, cancer-associated pain, and tumor development.

The findings suggest that cannabinoids can be used to address some side effects of cancer and to limit the growth of tumors, though a lack of supporting clinical trials presents a challenge for use on actual patients. An additional challenge will be examining whether any of the over one hundred naturally occurring cannabinoids or dozens of synthetic compounds also exhibit useful clinical properties.

Currently, clinical trials are underway; however, no regulatory agencies have approved cannabinoid use for any cancer symptoms beyond antinausea.”

https://pubmed.ncbi.nlm.nih.gov/38203245/

https://www.mdpi.com/1422-0067/25/1/74

Anti-proliferative effect of Cannabidiol in Prostate cancer cell PC3 is mediated by apoptotic cell death, NFκB activation, increased oxidative stress, and lower reduced glutathione status

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“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

Cannabidiol Inhibits the Proliferation and Invasiveness of Prostate Cancer Cells

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“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

A Phase I Dose Escalation and Expansion Study of Epidiolex (Cannabidiol) in Patients with Biochemically Recurrent Prostate Cancer

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“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

Therapeutic targeting of the tumor microenvironments with cannabinoids and their analogs: Update on clinical trials

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“Cancer is a major global public health concern that affects both industrialized and developing nations. Current cancer chemotherapeutic options are limited by side effects, but plant-derived alternatives and their derivatives offer the possibilities of enhanced treatment response and reduced side effects.

A plethora of recently published articles have focused on treatments based on cannabinoids and cannabinoid analogs and reported that they positively affect healthy cell growth and reverse cancer-related abnormalities by targeting aberrant tumor microenvironments (TMEs), lowering tumorigenesis, preventing metastasis, and/or boosting the effectiveness of chemotherapy and radiotherapy.

Furthermore, TME modulating systems are receiving much interest in the cancer immunotherapy field because it has been shown that TMEs have significant impacts on tumor progression, angiogenesis, invasion, migration, epithelial to mesenchymal transition, metastasis and development of drug resistance.

Here, we have reviewed the effective role of cannabinoids, their analogs and cannabinoid nano formulations on the cellular components of TME (endothelial cells, pericytes, fibroblast and immune cells) and how efficiently it retards the progression of carcinogenesis is discussed. The article summarizes the existing research on the molecular mechanisms of cannabinoids regulation of the TME and finally highlights the human studies on cannabinoids’ active interventional clinical trials.

The conclusion outlines the need for future research involving clinical trials of cannabinoids to demonstrate their efficacy and activity as a treatment/prevention for various types of human malignancies.”

https://pubmed.ncbi.nlm.nih.gov/37146933/

https://www.sciencedirect.com/science/article/abs/pii/S0013935123006540?via%3Dihub

Cannabidiol and Cannabis Sativa as a potential treatment in vitro prostate cancer cells silenced with RBBp6 and PC3 xenograft

SpringerLink

“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

Cannabidiol alters mitochondrial bioenergetics via VDAC1 and triggers cell death in hormone-refractory prostate cancer

Pharmacological Research

“In spite of the huge advancements in both diagnosis and interventions, hormone refractory prostate cancer (HRPC) remains a major hurdle in prostate cancer (PCa). Metabolic reprogramming plays a key role in PCa oncogenesis and resistance. However, the dynamics between metabolism and oncogenesis are not fully understood.

Here, we demonstrate that two multi-target natural products, cannabidiol (CBD) and cannabigerol (CBG), suppress HRPC development in the TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model by reprogramming metabolic and oncogenic signalling.

Mechanistically, CBD increases glycolytic capacity and inhibits oxidative phosphorylation in enzalutamide-resistant HRPC cells. This action of CBD originates from its effect on metabolic plasticity via modulation of VDAC1 and hexokinase II (HKII) coupling on the outer mitochondrial membrane, which leads to strong shifts of mitochondrial functions and oncogenic signalling pathways.

The effect of CBG on enzalutamide-resistant HRPC cells was less pronounced than CBD and only partially attributable to its action on mitochondria. However, when optimally combined, these two cannabinoids exhibited strong anti-tumor effects in TRAMP mice, even when these had become refractory to enzalutamide, thus pointing to their therapeutical potential against PCa.”

https://pubmed.ncbi.nlm.nih.gov/36736415/

https://www.sciencedirect.com/science/article/pii/S1043661823000397?via%3Dihub

The antitumor activity of cannabis sativa and CBD in prostate cancer PC3 cells

Cancer Research

“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. 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 tumor 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 tumors 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://aacrjournals.org/cancerres/article/82/12_Supplement/3714/701192

Association between cannabis use with urological cancers: A population-based cohort study and a mendelian randomization study in the UK biobank

“Background: Legislation of cannabis use has been approved in many European and North American countries. Its impact on urological cancers is unclear. This study was conducted to explore the association between cannabis use and the risk of urological cancers.

Methods: We identified 151,945 individuals with information on cannabis use in the UK Biobank from 2006 to 2010. Crude and age-standardized incidence ratios of different urological cancers were evaluated in the entire cohort and subgroups. Cox regression was performed for survival analysis.

Results: Previous use of cannabis was a significant protective factor for renal cell carcinoma (HR = 0.61, 95%CI:0.40-0.93, p = 0.021) and prostate cancer (HR = 0.82, 95%CI:0.73-0.93, p = 0.002) in multivariable analysis. The association between previous cannabis use and both renal cell carcinoma and bladder cancer was only observed in females (HRRCC = 0.42, 95%CI:0.19-0.94, p = 0.034; HRBCa = 0.43, 95%CI:0.21-0.86, p = 0.018) but not in men. There was no significant association between cannabis use and testicular cancer incidence. Mendelian randomization demonstrated a potential causal effect of cannabis use on a lower incidence of renal cell carcinoma.

Conclusions: Previous use of cannabis was associated with a lower risk of bladder cancer, renal cell carcinoma, and prostate cancer. The inverse association between cannabis and both renal cell carcinoma and bladder cancer was only found in females but not in males.”

https://pubmed.ncbi.nlm.nih.gov/35975633/

“Cannabis, also known as marijuana, is the most used substance derived from Cannabis Sativa which can be used for recreational or medical purposes. Some evidence also suggested that cannabinoids might induce apoptosis of cancer cells and inhibit oncogenesis, indicating a potential treatment effect”

https://onlinelibrary.wiley.com/doi/10.1002/cam4.5132

“Previous Cannabis Use Linked to Lower Risk of Some Genitourinary Cancers”

https://www.cancertherapyadvisor.com/home/cancer-topics/urologic-cancers/genitourinary-cancers-previous-cannabis-use-lower-risk/

The Effectiveness and Safety of Medical Cannabis for Treating Cancer Related Symptoms in Oncology Patients

Frontiers in Pain Research (@FrontPain) / Twitter

“The use of medical cannabis (MC) to treat cancer-related symptoms is rising. However, there is a lack of long-term trials to assess the benefits and safety of MC treatment in this population. In this work, we followed up prospectively and longitudinally on the effectiveness and safety of MC treatment.

Oncology patients reported on multiple symptoms before and after MC treatment initiation at one-, three-, and 6-month follow-ups. Oncologists reported on the patients’ disease characteristics. Intention-to-treat models were used to assess changes in outcomes from baseline. MC treatment was initiated by 324 patients and 212, 158 and 126 reported at follow-ups.

Most outcome measures improved significantly during MC treatment for most patients (p < 0.005). Specifically, at 6 months, total cancer symptoms burden declined from baseline by a median of 18%, from 122 (82–157) at baseline to 89 (45–138) at endpoint (−18.98; 95%CI= −26.95 to −11.00; p < 0.001). Reported adverse effects were common but mostly non-serious and remained stable during MC treatment.

The results of this study suggest that MC treatment is generally safe for oncology patients and can potentially reduce the burden of associated symptoms with no serious MC-related adverse effects.

The main finding of the current study is that most cancer comorbid symptoms improved significantly during 6 months of MC treatment.

Additionally, we found that MC treatment in cancer patients was well tolerated and safe.”

https://pubmed.ncbi.nlm.nih.gov/35669038/

https://www.frontiersin.org/articles/10.3389/fpain.2022.861037/full?utm_source=fweb

“Cancer Pain Treatment Using Marijuana Safe and Effective, Large Study Finds”

https://www.newsweek.com/cannabis-medicinal-cancer-patient-symptoms-pain-relief-1711981