Category Archives: Cancer

Decreased melanoma CSF-1 secretion by Cannabigerol treatment reprograms regulatory myeloid cells and reduces tumor progression

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“During solid tumor progression, the tumor microenvironment (TME) evolves into a highly immunosuppressive milieu. Key players in the immunosuppressive environment are regulatory myeloid cells, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), which are recruited and activated via tumor-secreted cytokines such as colony-stimulating factor 1 (CSF-1). Therefore, the depletion of tumor-secreted cytokines is a leading anticancer strategy. Here, we found that CSF-1 secretion by melanoma cells is decreased following treatment with Cannabis extracts. Cannabigerol (CBG) was identified as the bioactive cannabinoid responsible for the effects. Conditioned media from cells treated with pure CBG or the high-CBG extract reduced the expansion and macrophage transition of the monocytic-MDSC subpopulation. Treated MO-MDSCs also expressed lower levels of iNOS, leading to restored CD8+ T-cell activation. Tumor-bearing mice treated with CBG presented reduced tumor progression, lower TAM frequencies and reduced TAM/M1 ratio. A combination of CBG and αPD-L1 was more effective in reducing tumor progression, enhancing survival and increasing the infiltration of activated cytotoxic T-cells than each treatment separately. We show a novel mechanism for CBG in modulating the TME and enhancing immune checkpoint blockade therapy, underlining its promising therapeutic potential for the treatment of a variety of tumors with elevated CSF-1 expression.”

https://pubmed.ncbi.nlm.nih.gov/37325437/

“Our findings have immediate practical implications; current treatment protocols that are already in combination with medical Cannabis as palliative care can select the CBG-rich chemovars in combination with immune checkpoint blockade therapy, making it more effective, and providing patients with antitumor properties in addition to the palliative ones.”

https://www.tandfonline.com/doi/full/10.1080/2162402X.2023.2219164

Exosomal delivery of cannabinoids against cancer

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“Exosomes are extracellular vesicles (EVs) originating from endosomes that play a role in cellular communication. These vesicles which mimic the parental cells that release them are promising candidates for targeted drug delivery and therapeutic applications against cancer because of their favorable biocompatibility, specific targeting, low toxicity, and immunogenicity.

Currently, Delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD) and other cannabinoids (e.g., CBG, THCV, CBC), are being explored for their anticancer and anti-proliferative properties. Several mechanisms, including cell cycle arrest, proliferation inhibition, activation of autophagy and apoptosis, inhibition of adhesion, metastasis, and angiogenesis have been proposed for their anticancer activity. EVs could be engineered as cannabinoid delivery systems for tumor-specificity leading to superior anticancer effects.

This review discusses current techniques for EV isolation from various sources, characterization and strategies to load them with cannabinoids. More extensively, we culminate information available on different sources of EVs that have anticancer activity, mechanism of action of cannabinoids against various wild type and resistant tumors and role of CBD in histone modifications and cancer epigenetics. We have also enumerated the role of EVs containing cannabinoids against various tumors and in chemotherapy induced neuropathic pain.”

https://pubmed.ncbi.nlm.nih.gov/37257632/

https://www.sciencedirect.com/science/article/abs/pii/S0304383523001945?via%3Dihub

Use of Medical Cannabis by Patients with Cancer: Attitudes, Knowledge, and Practice

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“Objectives: The study sought to assess factors contributing to the demand for MC among patients with cancer.

Methods: Patients applying for a permit to receive MC at a pain and palliative clinic of a university-affiliated cancer center in Israel in 2020-2021 were asked to complete self-report questionnaires assessing attitudes, knowledge, and expectations regarding MC use. Findings were compared between first-time and repeat applicants. Repeat applicants were asked to report their indications for requesting MC, patterns of use, and treatment effect.

Results: The cohort included 146 patients: 63 first-time applicants and 83 repeat applicants. First-time applicants were more likely to consult sources other than their oncologist for MC-related information (p <.01) and expressed more concern about addiction (p <.001) and side effects (p <.05). They often erroneously assumed the treatment was subsidized (p <.001). Repeat applicants were younger (p <.05) and included more smokers (p <.05) and recreational cannabis users (p <.05); 56.6% were cancer survivors and 78% used high-potency MC. Most patients believed to some degree that MC is more effective than conventional medications for symptom control, and over half thought that MC helps to cure cancer.

Conclusion: Misconceptions regarding the effectiveness of MC for symptom management and treatment may explain the motivation of patients with cancer to apply for a permit. There seems to be an association of young age, cigarette smoking, and recreational cannabis use with ongoing use of MC among cancer survivors.”

https://pubmed.ncbi.nlm.nih.gov/37244526/

https://www.jpsmjournal.com/article/S0885-3924(23)00514-6/fulltext

Antitumor Effects of Cannabis sativa Bioactive Compounds on Colorectal Carcinogenesis

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“Cannabis sativa is a multipurpose plant that has been used in medicine for centuries. Recently, considerable research has focused on the bioactive compounds of this plant, particularly cannabinoids and terpenes. Among other properties, these compounds exhibit antitumor effects in several cancer types, including colorectal cancer (CRC). Cannabinoids show positive effects in the treatment of CRC by inducing apoptosis, proliferation, metastasis, inflammation, angiogenesis, oxidative stress, and autophagy. Terpenes, such as β-caryophyllene, limonene, and myrcene, have also been reported to have potential antitumor effects on CRC through the induction of apoptosis, the inhibition of cell proliferation, and angiogenesis. In addition, synergy effects between cannabinoids and terpenes are believed to be important factors in the treatment of CRC. This review focuses on the current knowledge about the potential of cannabinoids and terpenoids from C. sativa to serve as bioactive agents for the treatment of CRC while evidencing the need for further research to fully elucidate the mechanisms of action and the safety of these compounds.”

https://pubmed.ncbi.nlm.nih.gov/37238634/

“Data suggest that cannabinoids exert advantages in the treatment of CRC, mostly by inducing apoptosis, although some evidence also points out that they may target other key therapeutic events, such as proliferation, metastasis, inflammation, angiogenesis, oxidative stress, and autophagy. The currently available data on this subject refer mostly to the C. sativa major cannabinoids, i.e., CBD, THC, and CBG, but several pieces of evidence suggest that minor cannabinoids and other bioactive compounds such as terpenes also may hold potential as therapeutic agents for CRC. Data also suggest that certain combinations of cannabinoids and terpenes in C. sativa extracts can lead to a synergistic action known as the “entourage effect,” which has been linked to certain pharmacological benefits. The potential therapeutic benefits of the cannabinoids and terpenes from this plant make them key candidates for further drug development.”

https://www.mdpi.com/2218-273X/13/5/764

Cannabinoids Reduce Melanoma Cell Viability and Do Not Interfere with Commonly Used Targeted Therapy in Metastatic Melanoma In Vivo and In Vitro

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“Background: Cannabinoids are mainly used for recreational purposes, but also made their way into oncology, since these substances can be taken to increase appetite in tumour cachexia. Since there are some hints in the literature that cannabinoids might have some anti-cancerous effects, the aim of this study was to study if and how cannabinoids mediate pro-apoptotic effects in metastatic melanoma in vivo and in vitro and its value besides conventional targeted therapy in vivo. 

Methods: Several melanoma cell lines were treated with different concentrations of cannabinoids, and anti-cancerous efficacy was assessed by proliferation and apoptosis assays. Subsequent pathway analysis was performed using apoptosis, proliferation, flow cytometry and confocal microscopy data. The efficacy of cannabinoids in combination with trametinib was studied in NSG mice in vivo. 

Results: Cannabinoids reduced cell viability in multiple melanoma cell lines in a dose-dependent way. The effect was mediated by CB1, TRPV1 and PPARα receptors, whereby pharmacological blockade of all three receptors protected from cannabinoid-induced apoptosis. Cannabinoids initiated apoptosis by mitochondrial cytochrome c release with consecutive activation of different caspases. Essentially, cannabinoids significantly decreased tumour growth in vivo and were as potent as the MEK inhibitor trametinib. 

Conclusions: We could demonstrate that cannabinoids reduce cell viability in several melanoma cell lines, initiate apoptosis via the intrinsic apoptotic pathway by cytochrome c release and caspase activation and do not interfere with commonly used targeted therapy.”

https://pubmed.ncbi.nlm.nih.gov/37237519/

“Cannabinoids are mainly used for recreational purposes but find their way into oncology due to ongoing legalization efforts and anti-cancerous hints in the scientific literature. The goal of this study was to elucidate the mode of action of a clinically used cannabis medication in metastatic melanoma as well as its clinical value in combination with targeted therapy. By cell viability and apoptosis assays, we could demonstrate that cannabinoids mediate their apoptotic effect in a caspase-mediated fashion by disturbing mitochondrial integrity. With in vivo experiments, we could demonstrate that clinically used cannabinoid medication does not interfere with the commonly used anti-cancerous drug trametinib. Our results suggest that cannabinoids are effective in metastatic melanoma and pave the way for further clinical trials.”

https://www.mdpi.com/2079-7737/12/5/706

Cannabis sativa L. modulates altered metabolic pathways involved in key metabolisms in human breast cancer (MCF-7) cells: A metabolomics study

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“The present study investigated the ability of Cannabis sativa leaves infusion (CSI) to modulate major metabolisms implicated in cancer cells survival, as well as to induce cell death in human breast cancer (MCF-7) cells. MCF-7 cell lines were treated with CSI for 48 h, doxorubicin served as the standard anticancer drug, while untreated MCF-7 cells served as the control. CSI caused 21.2% inhibition of cell growth at the highest dose. Liquid chromatography-mass spectroscopy (LC-MS) profiling of the control cells revealed the presence of carbohydrate, vitamins, oxidative, lipids, nucleotides, and amino acids metabolites. Treatment with CSI caused a 91% depletion of these metabolites, while concomitantly generating selenomethionine, l-cystine, deoxyadenosine triphosphate, cyclic AMP, selenocystathionine, inosine triphosphate, adenosine phosphosulfate, 5′-methylthioadenosine, uric acid, malonic semialdehyde, 2-methylguanosine, ganglioside GD2 and malonic acid. Metabolomics analysis via pathway enrichment of the metabolites revealed the activation of key metabolic pathways relevant to glucose, lipid, amino acid, vitamin, and nucleotide metabolisms. CSI caused a total inactivation of glucose, vitamin, and nucleotide metabolisms, while inactivating key lipid and amino acid metabolic pathways linked to cancer cell survival. Flow cytometry analysis revealed an induction of apoptosis and necrosis in MCF-7 cells treated with CSI. High-performance liquid chromatography (HPLC) analysis of CSI revealed the presence of cannabidiol, rutin, cinnamic acid, and ferulic. These results portray the antiproliferative potentials of CSI as an alternative therapy for the treatment and management of breast cancer as depicted by its modulation of glucose, lipid, amino acid, vitamin, and nucleotide metabolisms, while concomitantly inducing cell death in MCF-7 cells.”

https://pubmed.ncbi.nlm.nih.gov/37215911/

https://www.cell.com/heliyon/fulltext/S2405-8440(23)03363-7?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2405844023033637%3Fshowall%3Dtrue

Effervescent cannabidiol solid dispersion-doped dissolving microneedles for boosted melanoma therapy via the “TRPV1-NFATc1-ATF3” pathway and tumor microenvironment engineering

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“Background: Conventional dissolving microneedles (DMNs) face significant challenges in anti-melanoma therapy due to the lack of active thrust to achieve efficient transdermal drug delivery and intra-tumoral penetration.

Methods: In this study, the effervescent cannabidiol solid dispersion-doped dissolving microneedles (Ef/CBD-SD@DMNs) composed of the combined effervescent components (CaCO3 & NaHCO3) and CBD-based solid dispersion (CBD-SD) were facilely fabricated by the “one-step micro-molding” method for boosted transdermal and tumoral delivery of cannabidiol (CBD).

Results: Upon pressing into the skin, Ef/CBD-SD@DMNs rapidly produce CO2 bubbles through proton elimination, significantly enhancing the skin permeation and tumoral penetration of CBD. Once reaching the tumors, Ef/CBD-SD@DMNs can activate transient receptor potential vanilloid 1 (TRPV1) to increase Ca2+ influx and inhibit the downstream NFATc1-ATF3 signal to induce cell apoptosis. Additionally, Ef/CBD-SD@DMNs raise intra-tumoral pH environment to trigger the engineering of the tumor microenvironment (TME), including the M1 polarization of tumor-associated macrophages (TAMs) and increase of T cells infiltration. The introduction of Ca2+ can not only amplify the effervescent effect but also provide sufficient Ca2+ with CBD to potentiate the anti-melanoma efficacy. Such a “one stone, two birds” strategy combines the advantages of effervescent effects on transdermal delivery and TME regulation, creating favorable therapeutic conditions for CBD to obtain stronger inhibition of melanoma growth in vitro and in vivo.

Conclusions: This study holds promising potential in the transdermal delivery of CBD for melanoma therapy and offers a facile tool for transdermal therapies of skin tumors.”

https://pubmed.ncbi.nlm.nih.gov/37198657/

“In summary, the novel Ef/CBD-SD@DMNs system developed in this study offers a promising approach to improve the efficacy of CBD-based therapy for melanoma. Ef/CBD-SD@DMNs combines the advantages of effervescence and CBD-based solid dispersion to achieve better transdermal and tumoral delivery of CBD. The in vitro and in vivo results demonstrate that Ef/CBD-SD@DMNs can not only effectively induce melanoma apoptosis via the “Ca2+ influx-NFATc1-ATF3” pathway but also activate the tumor microenvironment probably through increasing intra-tumoral pH environment. This study provides a facile and efficient design for a transdermal delivery system that may have a significant impact on the development of new melanoma therapies.”

https://biomaterialsres.biomedcentral.com/articles/10.1186/s40824-023-00390-x

Study of Cannabis Oils Obtained from Three Varieties of C. sativa and by Two Different Extraction Methods: Phytochemical Characterization and Biological Activities

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“Currently, much effort is being placed into obtaining extracts and/or essential oils from Cannabis sativa L. for specific therapeutic purposes or pharmacological compositions. These potential applications depend mainly on the phytochemical composition of the oils, which in turn are determined by the type of C. sativa and the extraction method used to obtain the oils.

In this work, we have evaluated the contents of secondary metabolites, delta-9-tetrahydrocannabinol (THC), and cannabidiol (CBD), in addition to the total phenolic, flavonoids, and anthraquinone content in oils obtained using solid-liquid extraction (SLE) and supercritical fluid extraction (SCF). Different varieties of C. sativa were chosen by using the ratio of THC to CBD concentrations. Additionally, antioxidant, antifungal and anticancer activities on different cancer cell lines were evaluated in vitro.

The results indicate that oils extracted by SLE, with high contents of CBD, flavonoids, and phenolic compounds, exhibit a high antioxidant capacity and induce a high decrease in the cell viability of the tested breast cancer cell line (MCF-7). The observed biological activities are attributed to the entourage effect, in which CBD, phenols and flavonoids play a key role. Therefore, it is concluded that the right selection of C. sativa variety and the solvent for SLE extraction method could be used to obtain the optimal oil composition to develop a natural anticancer agent.”

https://pubmed.ncbi.nlm.nih.gov/37176831/

“Different varieties of C. sativa identified by the ratio of THC:CBD were used to extract cannabis oil using two extraction methods. The evaluation of the biological activities of the oils indicates that they are mostly determined by their chemical composition. For example, all Cannabis oils exhibit an antioxidant capacity and antiproliferative effects on tested cancer cell lines. In both types of experiments, the most active Cannabis oil tested was M4, suggesting a direct relationship between its antioxidant capacity and cancer cell cytotoxicity. In addition, M4 exhibits a high selectivity against breast cancer cell lines, and, therefore, Cannabis oils can be considered potential anticancer agents.”

https://www.mdpi.com/2223-7747/12/9/1772

Cannabinoid compounds in combination with curcumin and piperine display an anti-tumorigenic effect against colon cancer cells

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“Currently, use of cannabinoids is limited to improve adverse effects of chemotherapy and their palliative administration during treatment is curiously concomitant with improved prognosis and regressed progression in patients with different tumor types. Although, non-psychoactive cannabidiol (CBD) and cannabigerol (CBG) display antineoplastic effects by repressing tumor growth and angiogenesis both in cell line and animal models, their use as chemotherapeutic agents is awaiting further investigation. Both clinical and epidemiological evidence supported by experimental findings suggest that micronutrients such as curcumin and piperine may present a safer strategy in preventing tumorigenesis and its recurrence. Recent studies demonstrated that piperine potentiates curcumin’s inhibitory effect on tumor progression via enhancing its delivery and therapeutic activity. In this study, we investigated a plausible therapeutic synergism of a triple combination of CBD/CBG, curcumin, and piperine in the colon adenocarcinoma using HCT116 and HT29 cell lines. Potential synergistic effects of various combinations including these compounds were tested by measuring cancer cell proliferation and apoptosis. Our findings revealed that different genetic backgrounds of HCT116 and HT29 cell lines resulted in divergent responses to the combination treatments. Triple treatment showed synergism in terms of exhibiting anti-tumorigenic effects by activating the Hippo YAP signaling pathway in the HCT116 cell line.”

https://pubmed.ncbi.nlm.nih.gov/37180710/

“This study demonstrates that combination of curcumin, piperine and cannabinoid variants inhibit cell proliferation and induce apoptosis drastically in distinct models of colorectal cancer. Intriguingly, our findings point out that the compounds of interest, each of which are already known for their anti-tumorigenic and preventive role in colon cancer as single agents, displayed an augmented therapeutic effect in the cell lines tested. In the HT29 cell line, CBG significantly reduced cell proliferation and induced apoptosis as a monotherapy agent, whereas these anti-tumorigenic effects were overridden in the presence of curcumin/piperine. Therefore, findings from this study suggest a benefit in using cannabinoid compounds as single anti-cancer agents in the treatment of those colon carcinoma tumors that carry a genetic profile similar to that of the HT29 cell line. One major limitation of the current study was to reconcile these findings with the cannabinoid receptor 1 (CB1 receptor) and cannabinoid receptor 2 (CB2 receptor) expression profile of the cell lines used. Therefore, in future studies the link between the anti-tumorigenic effects of single cannabinoid compounds or their cocktails and the cannabinoid receptor expression should be interrogated to shed light on the differences in the responses of these cells to distinct cannabinoid-based regimens. In addition to the cannabinoid receptor status, role of other mutations in driver genes should be subject to more rigorous mechanistic studies to fully understand their role in determining the drug mechanism of action and the response to distinct treatment schemes involving cannabinoids as single agents their various combinations.”

https://www.frontiersin.org/articles/10.3389/fphar.2023.1145666/full

Cannabidiol as a Promising Adjuvant Therapy for Estrogen Receptor-Positive Breast Tumors: Unveiling Its Benefits with Aromatase Inhibitors

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“Background: Estrogen receptor-positive (ER+) breast cancer is the most diagnosed subtype, with aromatase inhibitors (AIs) being one of the therapeutic drug types used in the clinic. However, endocrine resistance may develop after prolonged treatment, and different approaches, such as combining endocrine and targeted therapies, have been applied. Recently, we demonstrated that cannabidiol (CBD) induces anti-tumor actions in ER+ breast cancer cells by targeting aromatase and ERs. Considering this, we studied, in vitro, whether CBD when combined with AIs could improve their effectiveness.

Methods: MCF-7aro cells were used and the effects on cell viability and on the modulation of specific targets were investigated.

Results: CBD when combined with anastrozole (Ana) and letrozole (Let) caused no beneficial effect in comparison to the isolated AIs. In contrast, when combined with the AI exemestane (Exe), CBD potentiated its pro-cell death effects, abolished its estrogen-like effect, impaired ERα activation, and prevented its oncogenic role on the androgen receptor (AR). Moreover, this combination inhibited ERK1/2 activation, promoting apoptosis. The study of the hormonal microenvironment suggests that this combination should not be applied in early stages of ER+ breast tumors.

Conclusions: Contrary to Ana and Let, this study highlights the potential benefits of combining CBD with Exe to improve breast cancer treatment and opens up the possibility of new therapeutic approaches comprising the use of cannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/37173983/

“Cannabidiol (CBD) has demonstrated important anti-tumor effects on ER+ breast cancer cells. Considering this, our goal was to evaluate the effects of combining CBD with the AIs currently in use in the clinical context. Our results revealed that CBD may be particularly beneficial when combined with the AI exemestane (Exe), since it potentiates the anti-tumor effects of Exe through the modulation of cell death and specific targets, including ERα and androgen receptor (AR). This reinforces the beneficial potential of cannabinoids in breast cancer and points to the possibility of improving Exe effects through an adjuvant therapy with CBD.”

https://www.mdpi.com/2072-6694/15/9/2517