Cannabinoid Cancer Biology and Prevention

Issue Cover

“Plant-based, synthetic, and endogenous cannabinoids have been shown to control a diverse array of biological processes, including regulation of cell fate across cancers. Their promise as broad-based antitumor agents in preclinical models has led to the initiation of pilot clinical trials. Session 5 of the National Cancer Institute’s Cannabis, Cannabinoids and Cancer Research Symposium provides an overview of this research topic.

Overall, the presentations highlight cannabinoid signal transduction and specific molecular mechanisms underlying cannabinoid antitumor activity. They also demonstrate the broad-based antitumor activity of the plant-based, synthetic, and endogenous cannabinoid compounds. Importantly, evidence is presented demonstrating when cannabinoids may be contraindicated as a treatment for cancer, as in the case of human papilloma virus-meditated oropharynx cancer or potentially other p38 MAPK pathway-driven cancers.

Finally, it is discussed that a key to advancing cannabinoids into the clinic is to conduct well-designed, large-scale clinical trials to determine whether cannabinoids are effective antitumor agents in cancer patients.”

https://pubmed.ncbi.nlm.nih.gov/34850900/

“These sessions present multiple lines of preclinical evidence supporting that the cannabinoids THC and CBD act as broad-based antitumor agents controlling many aspects of cancer progression, including cell proliferation, apoptosis, invasion, metastasis, and immune surveillance. “

https://academic.oup.com/jncimono/article/2021/58/99/6446216?login=false


Analysis of Potential Anti-Cancer Effects of Cannabinol and Cannabidiol using HCC1806 and HEK293 Cell Lines

URSCA 2018

“Humans produce endocannabinoids that act as neuromodulators in the endocannabinoid system. They bind to Gαi protein-coupled cannabinoid receptors to control the release of many neurotransmitters. Cannabinoids receptor 1 (CB1) mediates psychoactive effects through its location mostly in the central nervous system while Cannabinoid receptor 2 (CB2) regulates various immune responses through its location in peripheral tissues.

The endocannabinoid system has been used as a molecular target by research to treat diseases such as multiple sclerosis, cardiovascular disorders, obesity and inflammatory pain. Thus, the endocannabinoid system is a potential molecular target to treat cancer. With the proposed legalization of recreational marijuana and with growing number of patients using cannabis for medicinal purpose, there is an urgent need to provide data on potential medicinal value of cannabis and cannabinoids.

The Cannabis Sativa plant naturally synthesizes numerous different cannabinoids of which (CBN) and cannabidiol (CBD) have promising properties in cancer treatment. CBD is a phytocannabinoid known for its anticonvulsant and anti-nausea properties. Previous research suggests that CBD can target breast cancer cells while preserving normal cells. CBN is another phyotocannabinoid with anti-inflammatory properties that can potentially aid to reduce inflammation resulting from cancer.

This study aims to determine if CBN and CBD have an effect on cancer cells and normal cells. We hypothesize that we may observe an increase in apoptosis of cancer cells treated with the two compounds but no effect or perhaps even a slight increase in normal cell growth. Preliminary data in lab suggests that these compounds have anti-cancer properties and we want to solidify this evidence through repetition of the experiment.”

https://journals.macewan.ca/ursca/article/view/1582

Hemp ( Cannabis sativa L., Kompolti cv.) and Hop ( Humulus lupulus L., Chinook cv.) Essential Oil and Hydrolate: HS-GC-MS Chemical Investigation and Apoptotic Activity Evaluation

pharmaceuticals-logo

“In this study, essential oils (EOs) and hydrolates (Hys) from Italian hemp (Cannabis sativa L. Kompolti cv.) and hop (Humulus Lupulus L., Chinook cv.) supply chains were chemically characterized and tested to investigate their apoptotic potential for the first time. Headspace-Gas Chromatography-Mass Spectrometry (HS-GC-MS) techniques were performed to describe their volatile chemical profile, highlighting a composition rich in terpene derivatives such as monoterpenes and sesquiterpenes among which β-myrcene, limonene, β-caryophyllene and α-humulene were the main constituents of EOs; in contrast, linalool, cisp-menth-2,8-dien-1-ol, terpinen-4-ol, α-terpineol, caryophyllene oxide, and τ-cadinol were found in the Hys.

The cytotoxicity activity on human leukemia cells (HL60), human neuroblastoma cells (SH-SY5Y), human metastatic adenocarcinoma breast cells (MCF7), human adenocarcinoma breast cells (MDA), and normal breast epithelial cell (MCF10A) for the EOs and Hys was studied by MTT assay and cytofluorimetric analysis and scanning and transmission electron microscopy were performed to define ultrastructural changes and the mechanism of cells death for HL 60 cells.

An induction of the apoptotic mechanism was evidenced for hemp and hop EOs after treatment with the corresponding EC50 dose. In addition, TEM and SEM investigations revealed typical characteristics induced by the apoptotic pathway. Therefore, thanks to the integration of the applied methodologies with the used techniques, this work provides an overview on the metabolomic profile and the apoptotic potential of hemp and hop EOs and, for the first time, also of Hys.

The findings of this preliminary study confirm that the EOs and Hys from Cannabis and Humulus species are sources of bioactive molecules with multiple biological effects yet to be explored.”

https://pubmed.ncbi.nlm.nih.gov/36015124/

https://www.mdpi.com/1424-8247/15/8/976/htm

Evaluation of Sex Differences in the Potential of Δ 9-Tetrahydrocannabinol, Cannabidiol, Cannabidiolic Acid, and Oleoyl Alanine to Reduce Nausea-Induced Conditioned Gaping Reactions in Sprague-Dawley Rats

View details for Cannabis and Cannabinoid Research cover image

“Introduction: Cancer patients report nausea as a side effect of their chemotherapy treatment. Using the pre-clinical rodent model of acute nausea-lithium chloride (LiCl)-induced conditioned gaping-our group has demonstrated that exogenous cannabinoids may have antinausea potential. 

Materials and Methods: With the goal of evaluating the role of sex as a factor in pre-clinical research, we first compared the conditioned gaping reactions produced by varying doses of LiCl in male and female rats using the taste reactivity test (Experiment 1). 

Results: LiCl produced dose-dependent conditioned gaping similarly in male and female rats with the highest dose (127.2 mg/kg) producing robust conditioned gaping, with this dose used in subsequent experiments. Next, we examined the antinausea potential of THC (Experiment 2), CBD (Experiment 3), cannabidiolic acid (CBDA; Experiment 4) and oleoyl alanine (OlAla; Experiment 5) in both male and female rats. THC, CBD, CBDA, and OlAla dose dependently reduced conditioned gaping in both male and female rats in a similar manner. 

Conclusions: These results suggest that cannabinoids may be equally effective in treating nausea in both males and females.”

https://pubmed.ncbi.nlm.nih.gov/35984924/

https://www.liebertpub.com/doi/10.1089/can.2022.0158

Investigation of the Effects of the Endogenous Cannabinoid Anandamide on Luminal A Breast Cancer Cell Line MCF-7

“The present study was carried out to investigate anti-tumoral effects of Anandamide (AEA) in luminal A breast cancer cell line MCF-7. Cell viability was measured by MTT assay and cell index was measured by xCelligence DP analyzer system. The Feulgen method was used to determine the mitotic index parameter, and the 3H-Thymidine method was used to determine the labeling index parameter. The apoptotic index parameter was determined using a fluorescent dye DAPI. The results of this study showed that 25 µM Anandamide concentration was the optimum concentration for MCF-7 cells. While this concentration decreased the proportion of cells in the mitotic phase and synthesis phase, it increased the proportion of apoptotic cells.”

https://pubmed.ncbi.nlm.nih.gov/35988272/

https://www.cellmolbiol.org/index.php/CMB/article/view/4374

γ-Terpinene complexed with β-cyclodextrin attenuates spinal neuroactivity in animals with cancer pain by Ca2+ channel block

Research - The Pharmaceutical Journal

“Objectives: Considering that γ-terpinene (γ-TPN) is a monoterpene found in Cannabis oil, with high lipophilicity and limited pharmacokinetics, our objective was to evaluate whether its complexation in β-cyclodextrin (γ-TPN/β-CD) could improve its physicochemical properties and action on cancer pain, as well as verify the mechanisms of action involved.

Results: β-CD improved the physicochemical properties and prolonged the anti-hyperalgesic effect of γ-TPN. This compound also reduced the levels of IL-1β, TNF-α and iNOS in the tumour, and c-Fos protein in the spinal cord. In addition, it reduced Ca2+ current, presenting favourable chemical interactions with different voltage-dependent calcium channels.

Conclusion: These results indicate that the complexation of γ-TPN into β-CD increases its stability and time effect, reducing spinal neuroactivity and inflammation by blocking calcium channels.”

https://pubmed.ncbi.nlm.nih.gov/35976257/#affiliation-2

https://academic.oup.com/jpp/advance-article-abstract/doi/10.1093/jpp/rgac052/6670692?redirectedFrom=fulltext&login=false

Anticancer activity of Δ9-tetrahydrocannabinol and cannabinol in vitro and in human lung cancer xenograft

Asian Pacific Journal of Tropical Biomedicine

“Objective: To investigate the effects of Δ9-tetrahydrocannabinol, the principal psychoactive compound of Cannabis sativa, and cannabinol, a Δ9-tetrahydrocannabinol degradative product, on human non-small cell lung cancer cells.
Methods: Δ9-Tetrahydrocannabinol and cannabinol were tested for anticancer activity in human non-small cell lung cancer (A549) cells. The effects on cell proliferation, apoptosis, and phosphorylation profiles were examined. The effects of Δ9-tetrahydrocannabinol and cannabinol on tumor growth were also investigated using a xenograft nude mouse model. Apoptosis and targeted phosphorylation were verified by immunohistochemistry.
Results: Δ9-Tetrahydrocannabinol and cannabinol significantly inhibited cell proliferation and increased the number of apoptotic cells in a concentration-dependent manner. The Δ9-tetrahydrocannabinol- and cannabinol-treated cells had lower levels of phosphorylated protein kinase B [AKT (S473)], glycogen synthase kinase 3 alpha/beta, and endothelial nitric oxide synthase compared to the controls. The study of xenograft mice revealed that tumors treated with 15 mg/kg Δ9-tetrahydrocannabinol or 40 mg/kg cannabinol were significantly smaller than those of the control mice. The tumor progression rates in mice treated with 15 mg/kg Δ9-tetrahydrocannabinol or 40 mg/kg cannabinol were significantly slower than in the control group.
Conclusions: These findings indicate that Δ9-tetrahydrocannabinol and cannabinol inhibit lung cancer cell growth by inhibiting AKT and its signaling pathways, which include glycogen synthase kinase 3 alpha/beta and endothelial nitric oxide synthase.”

https://journals.lww.com/aptb/fulltext/2022/12080/anticancer_activity_of__9_tetrahydrocannabinol_and.1.aspx

In Vitro Anti-Proliferative Activity of Cannabis Extract on Human Cancer Cell Lines

“Background: Cannabis is classified as a Schedule 5 substance under the Narcotics Act B.E. 2522. Among with various modulatory effects of cannabinoids on body functions, two major cannabinoids are known to be used as medicines. They are a psychoactive delta-9-tetrahydrocannabinol (THC) and non-psychoactive cannabidiol (CBD). Currently, THC and CBD are advised to be used for treatment of a variety of medical conditions. Such as cell growth inhibition, anti-inflammatory effects and tumor regression. Although, potential benefit can be found in the medical condition above mentioned. The use of cannabis in some disease states such as cancer remain to be clinically evaluated in both efficacy and safety aspects through systematic research before being generalized for routine use.

Objective: The purpose of this study to investigate the In vitro effects of cannabis extracts on 10 types of human cancer cell line.

Methods: Two cannabis extracts (high THC level and high CBD level) were kept in sterile bottles, in refrigerator, until further use when it was dissolved in DMSO to give a stock solution, filtered and stored at 4 °C. The small percentage of DMSO present in the wells (maximal 0.1%) was found not to affect the experiment. The anti-proliferative activities of cannabis extract on cancer cell lines was determined by MTT assay.

Results: To evaluate the anti-proliferative activity of the cannabis extracts on 10 types of cancer cell line (lung cancer, breast cancer, colorectal cancer, gastric cancer, cervical cancer, ovarian cancer, liver cancer, pancreatic cancer, cholangiocarcinoma cancer, lymphoma cancer), the cells were treated with different concentrations of high THC level and high CBD level for 72h and cell viability was determined using MTT assay.

The results showed that all of cancer cell lines viability significantly reduced in concentration and time dependent manner following treatment with the extract. The IC50 of the high THC level values ranging from 10.80 ±1.03 to 54.60±1.27 μg/mL, and exhibited very strong activity against RBE with IC50 values of 10.80±1.03 μg/mL. The IC50 of the high CBD level values ranging from 6.00±1.16 to 26.00±1.37 μg/mL, and exhibited very strong activity against NCI-N87 with IC50 values of 6.00±1.16 μg/mL.

Conclusions: The results suggest that high THC level and high CBD level is a potent human cancer cells proliferation. Further investigations are needed to elucidate the mechanism of anticancer actions.”

https://he02.tci-thaijo.org/index.php/JDMS/article/view/255013

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/

Cannabinoids, Medical Cannabis, and Colorectal Cancer Immunotherapy

www.frontiersin.org

“Colorectal cancer is a major public health problem. Unfortunately, currently, no effective curative option exists for this type of malignancy. The most promising cancer treatment nowadays is immunotherapy which is also called biological or targeted therapy.

This type of therapy boosts the patient’s immune system ability to fight the malignant tumor. However, cancer cells may become resistant to immunotherapy and escape immune surveillance by obtaining genetic alterations. Therefore, new treatment strategies are required.

In the recent decade, several reports suggest the effectiveness of cannabinoids and Cannabis sativa extracts for inhibiting cancer proliferation in vitro and in vivo, including intestinal malignancies.

Cannabinoids were shown to modulate the pathways involved in cell proliferation, angiogenesis, programmed cell death and metastasis. Because of that, they are proposed as adjunct therapy for many malignancies. By far less information exists on the potential of the use of cannabis in combination with immunotherapy.

Here, we explore the possibility of the use of cannabinoids for modulation of immunotherapy of colon cancer and discuss possible advantages and limitations.”

https://pubmed.ncbi.nlm.nih.gov/34631734/

“Among new potential therapeutic approaches, treatment with cannabinoids and Cannabis sativa extracts have been shown to be efficient in inhibiting cancer growth in vitro and in vivo. It has been strongly suggested in the literature that cannabinoids and cannabis extracts can be used for the treatment of colorectal cancer. Evidence shows that cannabinoids have a high potential to be turned into promising drugs. It is obvious that these compounds can target the key signaling pathways of cancer development.”

https://www.frontiersin.org/articles/10.3389/fmed.2021.713153/full