Targeting carbohydrate metabolism in colorectal cancer – synergy between DNA-damaging agents, cannabinoids, and intermittent serum starvation

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“Chemotherapy is a therapy of choice for many cancers. However, it is often inefficient for long-term patient survival and is usually accompanied by multiple adverse effects. The adverse effects are mainly associated with toxicity to normal cells, frequently resulting in immune system depression, nausea, loss of appetite and metabolic changes.

In this respect, the combination of chemotherapy with cannabinoids, especially non-psychoactive, such as cannabidiol, cannabinol and other minor cannabinoids, as well as terpenes, may become very useful. This is especially pertinent because the mechanisms of anticancer effects of cannabinoids on cancer cells are often different from conventional chemotherapeutics.

In addition, cannabinoids help alleviate chemotherapy-induced adverse effects, regulate sleep and appetite, and are shown to have analgesic properties. Another component for achieving potential anti-cancer synergism is regulating nutrient availability and metabolism by calorie restriction and intermittent fasting in cancer cells. As tumours require a lot of energy to grow and because glucose is constantly available, malignant cells often opt to use glucose as a primary source of ATP production through substrate-level phosphorylation (fermentation) rather than through oxidative phosphorylation. Thus, periodic depletion of cancer cells of primary fuel, glucose, could result in a strong synergy in killing cancer cells by chemo- and possibly radiotherapy when combined with cannabinoids. This commentary will discuss what is known about such combinatorial treatments, including potential mechanisms and future protocols.”

https://pubmed.ncbi.nlm.nih.gov/39534512/

https://www.oncoscience.us/article/611/text/

Exploring the Potential of Synthetic Cannabinoids: Modulation of Biological Activity of Normal and Cancerous Human Colon Epithelial Cells

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“Colorectal cancer (CRC) is a global problem. Oncology currently practices conventional methods of treating this carcinoma, including surgery, chemotherapy, and radiotherapy. Unfortunately, their efficacy is low; hence, the exploration of new therapies is critical.

Recently, many efforts have focused on developing safe and effective anticancer compounds. Some of them include cannabinoids.

In the present study, we obtained cannabinoids, such as cannabidiol (CBD), abnormal cannabigerol (abn-CBG), cannabichromene (CBC), and cannabicitran (CBT), by chemical synthesis and performed the biological evaluation of their activity on colon cancer cells. In this study, we analyzed the effects of selected cannabinoids on the lifespan and metabolic activity of normal colonic epithelial cells and cancer colon cells.

This study demonstrated that cannabinoids can induce apoptosis in cancer cells by modulating mitochondrial dehydrogenase activity and cellular membrane integrity. The tested cannabinoids also influenced cell cycle progression. We also investigated the antioxidant activity of cannabinoids and established a relationship between the type of cannabinoid and nitric oxide (NO) production in normal and cancerous colon cells.

To conclude, it seems that, due to their interesting properties, the cannabinoids studied may constitute an interesting target for further research aimed at their use in alternative or combined therapies for human colon cancer.”

https://pubmed.ncbi.nlm.nih.gov/39404380/

“It seems that, due to their interesting properties, the cannabinoids studied may constitute an interesting target for further research, aimed at their use in alternative or combined therapies for human colon cancer.”

https://www.mdpi.com/2073-4409/13/19/1616

A Bioinformatic Analysis Predicts That Cannabidiol Could Function as a Potential Inhibitor of the MAPK Pathway in Colorectal Cancer

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“Colorectal cancer (CRC), found in the intestinal tract, is initiated and progresses through various mechanisms, including the dysregulation of signaling pathways. Several signaling pathways, such as EGFR and MAPK, involved in cell proliferation, migration, and apoptosis, are often dysregulated in CRC.

Although cannabidiol (CBD) has previously induced apoptosis and cell cycle arrest in vitro in CRC cell lines, its effects on signaling pathways have not yet been determined. An in silico analysis was used here to assess partner proteins that can bind to CBD, and docking simulations were used to predict precisely where CBD would bind to these selected proteins. A survey of the current literature was used to hypothesize the effect of CBD binding on such proteins.

The results predict that CBD could interact with EGFR, RAS/RAF isoforms, MEK1/2, and ERK1/2. The predicted CBD-induced inhibition might be due to CBD binding to the ATP binding site of the target proteins. This prevents the required phosphoryl transfer to activate substrate proteins and/or CBD binding to the DFG motif from taking place, thus reducing catalytic activity.”

https://pubmed.ncbi.nlm.nih.gov/39194723/

“This in silico study predicts that CBD could play a pivotal role in inhibiting the EGFR and MAPK pathways since almost all the proteins involved in this pathway interact with CBD. The most notable interactions occur between CBD and EGFR, KRAS, BRAF, and MEK1, as reflected by docking scores and being the most critically mutated or dysregulated proteins in colorectal cancer. CBD is proposed to act as an inhibitor of these proteins mainly by binding to the ATP catalytic binding site, which prevents phosphotransfer and the subsequent downstream activation of the substrate proteins. Secondly, CBD can act by binding to the DFG, which is adjacent to the hydrophobic pocket. The catalytic activity of this target protein is inhibited by this mechanism. Since the effect of CBD on these proteins has not yet been investigated, future studies should aim to determine if CBD indeed binds to these predicted target sites in these proteins and if the expected inhibitory effect occurs. Furthermore, in vitro phosphorylation studies on the selected proteins may determine if the phosphorylation of these proteins is affected by CBD treatment. In conclusion, CBD is predicted to interact with multiple role-players in the EGFR and MAPK pathways, potentially inhibiting these pathways and proteins.”

https://www.mdpi.com/1467-3045/46/8/506

Comparative Analysis of Polyphenolic Profile and Chemopreventive Potential of Hemp Sprouts, Leaves, and Flowers of the Sofia Variety

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“This study investigates the phytochemical composition and biological activities of hemp (Cannabis sativa L.) leaves, flowers’ methanolic extracts from the Sofia variety, and its sprouts cultivated under different light conditions (natural light, darkness, blue, and white LED light for 5, 7, and 9 days).

Phytochemical analysis using HPLC identified four key polyphenolic compounds in sprouts’ extracts: chlorogenic, caffeic, and gallic acids, and myricetin, with a predomination of the chlorogenic acid. In contrast, leaves and flowers’ extracts contained cannflavins A and B and chlorogenic, p-coumaric, and ferulic acids, with a significant presence of isochlorogenic acid. Antioxidant capacity, assessed by FRAP method, revealed higher antioxidant potential in leaves compared to flowers and sprouts, with sprouts grown under blue and white LED lights exhibiting the highest activity.

Cytotoxic activity was evaluated on human colon cancer cell lines (HT29, HCT116, DLD-1) and normal colon epithelial cells (CCD 841 CoN).

Results demonstrated significant and selective cytotoxicity against cancer cell lines, with leaves showing more pronounced effects than flowers, and sprouts only moderate activity. All samples revealed an anti-inflammatory effect in vitro.

To conclude, sprouts, leaves, and flowers of the Sofia hemp may be considered promising products for chemoprevention in the future.”

https://pubmed.ncbi.nlm.nih.gov/39124141/

“Cannabis sativa L. is a species of Asian origin that has been cultivated since ancient times for commercial, nutritional, and medicinal purposes.

The results indicate the interesting chemopreventive potential of sprouts, leaves, and flowers from Sofia hemp variety, manifested as cytotoxic, antioxidant, and anti-inflammatory activity.”

https://www.mdpi.com/2223-7747/13/15/2023

Integrated metabolomics and proteomics analyses to reveal anticancer mechanism of hemp oil extract in colorectal cancer

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“Cannabis sativa L., with a rich history in Chinese folk medicine, includes hemp strains that offer substantial economic and medical benefits due to their non-addictive properties.

Hemp has demonstrated various pharmaceutical activities, including anti-inflammatory, antioxidant, and anti-tumor effects.

This study explores the potential of hemp oil extract (HOE) in treating colorectal cancer (CRC). Despite its promise, the specific anticancer mechanisms of HOE have not been well understood. To elucidate these mechanisms, we employed mass spectrometry-based metabolomics and proteomics to investigate the global effects of HOE on CRC cells. Additionally, bioinformatics approaches, including bulk RNA-seq and single-cell RNA-seq, were used to identify gene expression differences and cellular heterogeneity. The results were validated using flow cytometry, western blotting, and immunohistochemistry.

Our findings reveal that HOE induces significant alterations in purine metabolism pathways, down-regulates c-MYC, and inhibits the expression of cell cycle-related proteins such as CCND1, CDK4, and CDK6, leading to cell cycle arrest in the G1 phase. This comprehensive analysis demonstrates that HOE effectively blocks the cell cycle in the G1 phase, thereby inhibiting colorectal cancer cell proliferation.

These findings provide experimental evidence supporting the potential therapeutic use of hemp in medicine.”

https://pubmed.ncbi.nlm.nih.gov/39059180/

“HOE effectively suppressed CRC cell proliferation both in vitro and in vivo.”

https://www.sciencedirect.com/science/article/abs/pii/S0731708524004199?via%3Dihub

Selected phytocannabinoids inhibit SN-38- and cytokine-evoked increases in epithelial permeability and improve intestinal barrier function in vitro

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“Irinotecan use is linked to the development of gastrointestinal toxicity and inflammation, or gastrointestinal mucositis. Selected phytocannabinoids have been ascribed anti-inflammatory effects in models of gastrointestinal inflammation, associated with maintaining epithelial barrier function.

We characterised the mucoprotective capacity of the phytocannabinoids: cannabidiol, cannabigerol, cannabichromene and cannabidivarin in a cell-based model of intestinal epithelial stress occurring in mucositis.

Transepithelial electrical resistance (TEER) was measured to determine changes in epithelial permeability in the presence of SN-38 (5 μM) or the pro-inflammatory cytokines TNFα and IL-1β (each at 100 ng/mL), alone or with concomitant treatment with each of the phytocannabinoids (1 μM). The DCFDA assay was used to determine the ROS-scavenging ability of each phytocannabinoid following treatment with the lipid peroxidant tbhp (200 μM).

Each phytocannabinoid provided significant protection against cytokine-evoked increases in epithelial permeability. Cannabidiol, cannabidivarin and cannabigerol were also able to significantly inhibit SN-38-evoked increases in permeability. None of the tested phytocannabinoids inhibited tbhp-induced ROS generation.

These results highlight a novel role for cannabidiol, cannabidivarin and cannabigerol as inhibitors of SN-38-evoked increases in epithelial permeability and support the rationale for the further development of novel phytocannabinoids as supportive therapeutics in the management of irinotecan-associated mucositis.”

https://pubmed.ncbi.nlm.nih.gov/38950639/

  • “•Phytocannabinoids may have efficacy in alleviating intestinal mucositis
  • •Cannabidiol, cannabidivarin, cannabichromene and cannabigerol (CBG) were tested for effects on intestinal epithelial permeability
  • •Intestinal epithelial Caco-2 cells were exposed to irinotecan metabolite SN-38 or cytokines with or without selected phytocannabinoids
  • •Phytocannabinoids variably protected against cytokine and SN-38-evoked increases in epithelial permeability without antioxidant effects
  • •Minor phytocannabinoids may contribute to mucoprotection and improve epithelial barrier function”

https://www.sciencedirect.com/science/article/pii/S0887233324001188?via%3Dihub

“Irinotecan, sold under the brand name Camptosar among others, is an anti-cancer medication used to treat colon cancer and small cell lung cancer. For colon cancer it is used either alone or with fluorouracil. For small cell lung cancer it is used with cisplatin. It is given intravenously.”

https://en.wikipedia.org/wiki/Irinotecan#:~:text=Irinotecan%2C%20sold%20under%20the%20brand,It%20is%20given%20intravenously.


Cannabis and cancer: unveiling the potential of a green ally in breast, colorectal, and prostate cancer

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“Cancer comes in second place on the list of causes of death worldwide. In 2018, the 5-year prevalence of breast cancer (BC), prostate cancer (PC), and colorectal cancer (CRC) were 30%, 12.3%, and 10.9%, respectively.

Cannabinoids are chemicals derived from the Cannabis sativa plant; the most investigated cannabinoids are cannabinol, delta 9-tetrahydrocannabinol (Δ9-THC), and cannabidiol. In humans, the endogenous endocannabinoid system consists of endocannabinoids, cannabinoids receptors (CBs), and enzymes that degrade the endocannabinoids.

In this review, we will review the most recent literature for evidence that discusses the role of cannabis in the treatment of the three types of neoplasms mentioned.

Studies have proved that BC cells express CB receptors; many in-vivo studies showed that cannabinoids cause apoptosis and inhibit proliferation and migration. Also, researchers found that treating BC mice with THC and JWH-133 (CB2 receptor agonist) slowed the tumor growth.

Regarding CRC, cannabidiol was found to decrease the viability of chemotherapy-resistant CRC cells and inhibit metastasis by antagonizing the G-protein-coupled receptor 55 (GPR55; a novel cannabinoid receptor) necessary for metastasis. Moreover, cannabidiol had anti-angiogenetic effects by reducing the expression of vascular endothelial growth factor (VEGF) in addition to anti-inflammatory effects.

Finally, studies demonstrated that PC cells highly express CB1 and CB2 receptors and that cannabinoids are capable of inhibiting the release of exosomes and microvesicles related to cancer progression. Cannabinoids also have antiproliferative, anti-invasive, anti-fibroblastic, cell cycle arrest, and proapoptotic effects on PC cells.”

https://pubmed.ncbi.nlm.nih.gov/38755733/

“There is growing evidence supporting the role of Cannabinoids in numerous pathological conditions, including their role in several cancer types such as breast, colorectal, and prostate cancer. Accordingly, cannabinoids could have a promising potential as adjunctive therapy for the treatment of these types of cancers.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-024-00233-z

Phytocannabinoids CBD, CBG, and their Derivatives CBD-HQ and CBG-A Induced In Vitro Cytotoxicity in 2D and 3D Colon Cancer Cell Models

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“Phytocannabinoids, compounds found in Cannabis sativa L., are used in oncology and palliative care to reduce the adverse reactions of standard therapies. Cancer patients use formulations of Cannabis sativa L. to manage the anxiety, pain, and nausea associated with cancer treatment, and there is growing evidence that some of them may exhibit anticancer properties.

In this study, we tested the anticancer potential of selected cannabinoids CBD (cannabidiol) and its quinone derivative CBD-HQ (cannabidiol hydroquinone), CBG (cannabigerol) and its acid derivative CBG-A (cannabigerolic acid), as well as a combination of CBD+CBG on the colon cancer cell line SW-620.

The MTT assay was used to determine the cannabinoids’ ability to induce colon cancer cell death. All cannabinoids were cytotoxic at the lowest concentration (3 μg/mL). The half maximal inhibitory concentration (IC50) ranged from 3.90 to 8.24 μg/mL, depending on the substance. Cytotoxicity was confirmed in a 3D spheroidal cell culture with calcein and propidium iodide staining. The amount of intracellular reactive oxygen species (ROS) was examined using a DCF-DA assay. CBG showed the lowest antioxidant activity of all the cannabinoids tested. The level of intracellular ROS decreased only by 0.7-18%. However, CBG-A induced the strongest reduction in ROS level by 31-39%.

Our results suggest that cannabinoids represent an interesting research direction with great implementation potential. These preliminary results represent the beginning of research into the potential of these substances for anticancer treatment and underscore the potential for further research.”

https://pubmed.ncbi.nlm.nih.gov/38666957/

“There is no doubt that phytocannabinoids represent an interesting research direction with great potential for implementation.”

https://www.mdpi.com/1467-3045/46/4/227

Targeting Colorectal Cancer: Unravelling the Transcriptomic Impact of Cisplatin and High-THC Cannabis Extract

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“Cisplatin and other platinum-derived chemotherapy drugs have been used for the treatment of cancer for a long time and are often combined with other medications. Unfortunately, tumours often develop resistance to cisplatin, forcing scientists to look for alternatives or synergistic combinations with other drugs.

In this work, we attempted to find a potential synergistic effect between cisplatin and cannabinoid delta-9-THC, as well as the high-THC Cannabis sativa extract, for the treatment of HT-29, HCT-116, and LS-174T colorectal cancer cell lines. However, we found that combinations of the high-THC cannabis extract with cisplatin worked antagonistically on the tested colorectal cancer cell lines. To elucidate the mechanisms of drug interactions and the distinct impacts of individual treatments, we conducted a comprehensive transcriptomic analysis of affected pathways within the colorectal cancer cell line HT-29.

Our primary objective was to gain a deeper understanding of the underlying molecular mechanisms associated with each treatment modality and their potential interactions. Our findings revealed an antagonistic interaction between cisplatin and high-THC cannabis extract, which could be linked to alterations in gene transcription associated with cell death (BCL2BADcaspase 10), DNA repair pathways (Rad52), and cancer pathways related to drug resistance.”

https://pubmed.ncbi.nlm.nih.gov/38674023/

“There is a need for new and better ways to prevent and treat it, possibly by combining different drugs. Recent research suggests that cannabinoids could be promising in this regard.”

https://www.mdpi.com/1422-0067/25/8/4439

Water Extracts from Industrial Hemp Waste Inhibit the Adhesion and Development of Candida Biofilm and Showed Antioxidant Activity on HT-29 Colon Cancer Cells

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“The evolution of regulatory perspectives regarding the health and nutritional properties of industrial hemp-based products (Cannabis sativa L.) has pushed research to focus on the development of new methods for both the extraction and formulation of the bioactive compounds present in hemp extracts. While the psychoactive and medicinal properties of hemp-derived cannabinoid extracts are well known, much less has been investigated on the functional and antimicrobial properties of hemp extracts.

Within the hemp value chain, various agricultural wastes and by-products are generated. These materials can be valorised through eco-innovations, ultimately promoting sustainable economic development. In this study, we explored the use of waste from industrial light cannabis production for the extraction of bioactive compounds without the addition of chemicals. The five extracts obtained were tested for their antimicrobial activity on both planktonic and sessile cells of pathogenic strains of the Candida albicansCandida parapsilosis, and Candida tropicalis species and for their antioxidant activity on HT-29 colon cancer cells under oxidative stress.

Our results demonstrated that these extracts display interesting properties both as antioxidants and in hindering the development of fungal biofilm, paving the way for further investigations into the sustainable valorisation of hemp waste for different biomedical applications.”

https://pubmed.ncbi.nlm.nih.gov/38612793/

https://www.mdpi.com/1422-0067/25/7/3979