Cannabidiol Induces Cell Death in Human Lung Cancer Cells and Cancer Stem Cells

“Currently, there is no effective therapy against lung cancer due to the development of resistance. Resistance contributes to disease progression, recurrence, and mortality. The presence of so-called cancer stem cells could explain the ineffectiveness of conventional treatment, and the development of successful cancer treatment depends on the targeting also of cancer stem cells. Cannabidiol (CBD) is a cannabinoid with anti-tumor properties. However, the effects on cancer stem cells are not well understood. The effects of CBD were evaluated in spheres enriched in lung cancer stem cells and adherent lung cancer cells. We found that CBD decreased viability and induced cell death in both cell populations. Furthermore, we found that CBD activated the effector caspases 3/7, increased the expression of pro-apoptotic proteins, increased the levels of reactive oxygen species, as well as a leading to a loss of mitochondrial membrane potential in both populations. We also found that CBD decreased self-renewal, a hallmark of cancer stem cells. Overall, our results suggest that CBD is effective against the otherwise treatment-resistant cancer stem cells and joins a growing list of compounds effective against cancer stem cells. The effects and mechanisms of CBD in cancer stem cells should be further explored to find their Achilles heel.”

https://pubmed.ncbi.nlm.nih.gov/34832951/

Role of Caryophyllane Sesquiterpenes in the Entourage Effect of Felina 32 Hemp Inflorescence Phytocomplex in Triple Negative MDA-MB-468 Breast Cancer Cells

“Cannabis sativa L. crops have been traditionally exploited as sources of fibers, nutrients, and bioactive phytochemicals of medical interest. In the present study, two terpene-rich organic extracts, namely FOJ and FOS, obtained from Felina 32 hemp inflorescences collected in June and September, respectively, have been studied for their in vitro anticancer properties. Particularly, their cytotoxicity was evaluated in different cancer cell lines, and the possible entourage effect between nonintoxicating phytocannabinoids (cannabidiol and cannabichromene) and caryophyllane sesquiterpenes (β-caryophyllene, β-caryophyllene oxide and α-humulene), as identified at GC/MS analysis, was characterized. Modulation of cannabinoid CB1 and CB2 receptors was studied as a mechanistic hypothesis. Results highlighted marked cytotoxic effects of FOJ, FOS, and pure compounds in triple negative breast cancer MDA-MB-468 cells, likely mediated by a CB2 receptor activation. Cannabidiol was the main cytotoxic constituent, although low levels of caryophyllane sesquiterpenes and cannabichromene induced potentiating effects; the presence in the extracts of unknown antagonistic compounds has been highlighted too. These results suggest an interest in Felina 32 hemp inflorescences as a source of bioactive phytocomplexes with anticancer properties and strengthen the importance of considering the possible involvement of minor terpenes, such as caryophyllane sesquiterpenes, in the entourage effect of hemp-based extracts.”

https://pubmed.ncbi.nlm.nih.gov/34771097/


Cannabidiol Suppresses Angiogenesis and Stemness of Breast Cancer Cells by Downregulation of Hypoxia-Inducible Factors-1α

pubmed logo

“To assess the effect of Cannabidiol (CBD) on the angiogenesis and stemness of breast cancer cells as well as proliferation.

Methods: mRNA level and the amount of protein of vascular endothelial growth factor (VEGF) were determined by qRT-PCR and ELISA. The angiogenic potential of breast cancer cells under hypoxic conditions was identified by the HUVEC tube formation assay. The degradation of HIF-1α by CBD and the Src/von Hippel-Lindau tumor suppressor protein (VHL) interaction were assessed by a co-immunoprecipitation assay and Western blotting. To identify the stemness of mamospheres, they were evaluated by the sphere-forming assay and flow cytometry.

Results: CBD can suppress angiogenesis and stem cell-like properties of breast cancer through Src/VHL/HIF-1α signaling. CBD may potentially be utilized in the treatment of refractory or recurrent breast cancer.”

https://pubmed.ncbi.nlm.nih.gov/34830821/

Simple Summary

“Cannabidiol (CBD), one of the compounds present in the marijuana plant, has antitumor properties. However, the effect of CBD on breast cancer remains unclear. The aim of this study was to assess the effects of CBD for the angiogenesis and stemness of breast cancer cells by decreasing the expression of hypoxia-induced factor-1α (HIF-1α) through the Src/von Hippel–Lindau tumor suppressor protein (VHL) interaction. CBD can suppress angiogenesis and stem cell-like properties of breast cancer through Src/VHL/HIF-1α signaling.”

https://www.mdpi.com/2072-6694/13/22/5667


Inhalant Cannabidiol Inhibits Glioblastoma Progression Through Regulation of Tumor Microenvironment


“Introduction: Glioblastoma (GBM) is the most common invasive brain tumor composed of diverse cell types with poor prognosis. The highly complex tumor microenvironment (TME) and its interaction with tumor cells play important roles in the development, progression, and durability of GBM. Angiogenic and immune factors are two major components of TME of GBM; their interplay is a major determinant of tumor vascularization, immune profile, as well as immune unresponsiveness of GBM. Given the ineffectiveness of current standard therapies (surgery, radiotherapy, and concomitant chemotherapy) in managing patients with GBM, it is necessary to develop new ways of treating these lethal brain tumors. Targeting TME, altering tumor ecosystem may be a viable therapeutic strategy with beneficial effects for patients in their fight against GBM. Materials and Methods: Given the potential therapeutic effects of cannabidiol (CBD) in a wide spectrum of diseases, including malignancies, we tested, for the first time, whether inhalant CBD can inhibit GBM tumor growth using a well-established orthotopic murine model. Optical imaging, histology, immunohistochemistry, and flow cytometry were employed to describe the outcomes such as tumor progression, cancer cell signaling pathways, and the TME. Results: Our findings showed that inhalation of CBD was able to not only limit the tumor growth but also to alter the dynamics of TME by repressing P-selectin, apelin, and interleukin (IL)-8, as well as blocking a key immune checkpoint-indoleamine 2,3-dioxygenase (IDO). In addition, CBD enhanced the cluster of differentiation (CD) 103 expression, indicating improved antigen presentation, promoted CD8 immune responses, and reduced innate Lymphoid Cells within the tumor. Conclusion: Overall, our novel findings support the possible therapeutic role of inhaled CBD as an effective, relatively safe, and easy to administer treatment adjunct for GBM with significant impacts on the cellular and molecular signaling of TME, warranting further research.”

https://pubmed.ncbi.nlm.nih.gov/34918964/

https://www.liebertpub.com/doi/10.1089/can.2021.0098

Perspectives of pediatric oncologists and palliative care physicians on the therapeutic use of cannabis in children with cancer

Cancer Reports“Background: Children with cancer are increasingly using cannabis therapeutically.

Aim: The purpose of this study was to determine the perspectives and practices of pediatric oncologists and palliative care physicians regarding the use of cannabis for medical purposes among children with cancer.

Methods: A self-administered, voluntary, cross-sectional, deidentified online survey was sent to all pediatric oncologists and palliative care physicians in Canada between June and August 2020. Survey domains included education, knowledge, and concerns about cannabis, views on its effectiveness, and the importance of cannabis-related research. Data were analyzed using descriptive statistics.

Results: In total, 122/259 (47.1%) physicians completed the survey. Although 62.2% of the physicians completed some form of training about medical cannabis, nearly all (95.8%) desired to know more about the dosing, side effects, and safety of cannabis. Physicians identified a potential role of cannabis in the management of nausea and vomiting (85.7%), chronic pain (72.3%), cachexia/poor appetite (67.2%), and anxiety or depression (42.9%). Only four (0.3%) physicians recognized cannabis to be potentially useful as an anticancer agent. Nearly all physicians reported that cannabis-related research for symptom relief is essential (91.5%) in pediatric oncology, whereas 51.7% expressed that future studies are necessary to determine the anticancer effects of cannabis.

Conclusions: Our findings indicate that most pediatric oncologists and palliative care physicians recognize a potential role for cannabis in symptom control in children with cancer. Well-conducted studies are required to create evidence for cannabis use and promote shared decision making with pediatric oncology patients and their caregivers.”

https://pubmed.ncbi.nlm.nih.gov/34672127/

“Several important implications from our findings include an urgent call for research and the development of clinical practice guidelines to support families and health care providers advising on the use of cannabis products in pediatric oncology. Funding agencies would be wise to provide direct funding opportunities for cannabis research in cancer, particularly among pediatric oncology populations where interest and use are rapidly outpacing the generation of rigorous evidence on dosing, efficacy, and safety.”

https://onlinelibrary.wiley.com/doi/10.1002/cnr2.1551

β-Caryophyllene Induces Apoptosis and Inhibits Angiogenesis in Colorectal Cancer Models

ijms-logo“Beta-Caryophyllene (BCP), a naturally occurring sesquiterpene abundantly found in cloves, hops, and cannabis, is the active candidate of a relatively new group of vascular-inhibiting compounds that aim to block existing tumor blood vessels.

Previously, we have reported the anti-cancer properties of BCP by utilizing a series of in-vitro anti-tumor-related assays using human colorectal carcinoma cells. The present study aimed to investigate the effects of BCP on in-vitro, ex-vivo, and in-vivo models of anti-angiogenic assays and evaluate its anti-cancer activity in xenograft tumor (both ectopic and orthotopic) mice models of human colorectal cancer.

BCP showed a remarkable reduction in tumor size and fluorescence molecular tomography signal intensity in all the mice treated with BCP, in a dose-dependent relationship, in ectopic and orthotopic tumor xenograft models, respectively. The histological analysis of the tumor from BCP-treated mice revealed a clear reduction of the density of vascularization. In addition, BCP induced apoptosis through downregulation of HSP60, HTRA, survivin, and XIAP, along with the upregulation of p21 expressions.

These results suggest that BCP acts at multiple stages of angiogenesis and could be used as a promising therapeutic candidate to halt the growth of colorectal tumor cells.”

https://pubmed.ncbi.nlm.nih.gov/34638895/

https://www.mdpi.com/1422-0067/22/19/10550

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”   http://www.ncbi.nlm.nih.gov/pubmed/23138934

“Beta-caryophyllene is a dietary cannabinoid.”   https://www.ncbi.nlm.nih.gov/pubmed/18574142

Lung cancer patient who had declined conventional cancer treatment: could the self-administration of ‘CBD oil’ be contributing to the observed tumour regression?

b-on, bliblioteca do conhecimento online | BMJ“Conventional lung cancer treatments include surgery, chemotherapy and radiotherapy; however, these treatments are often poorly tolerated by patients. Cannabinoids have been studied for use as a primary cancer treatment. Cannabinoids, which are chemically similar to our own body’s endocannabinoids, can interact with signalling pathways to control the fate of cells, including cancer cells. We present a patient who declined conventional lung cancer treatment. Without the knowledge of her clinicians, she chose to self-administer ‘cannabidiol (CBD) oil’ orally 2-3 times daily. Serial imaging shows that her cancer reduced in size progressively from 41 mm to 10 mm over a period of 2.5 years. Previous studies have failed to agree on the usefulness of cannabinoids as a cancer treatment. This case appears to demonstrate a possible benefit of ‘CBD oil’ intake that may have resulted in the observed tumour regression. The use of cannabinoids as a potential cancer treatment justifies further research.”

https://pubmed.ncbi.nlm.nih.gov/34649854/

“Patient’s perspective

“I was not very interested in traditional cancer treatments as I was worried about the risks of surgery, and I saw my late husband suffer through the side effects of radiotherapy. My relative suggested that I should try ‘cannabidiol (CBD) oil’ to treat my cancer, and I have been taking it regularly ever since. I am ‘over the moon’ with my cancer shrinking, which I believe was caused by the ‘CBD oil’. I am tolerating it very well and I intend to take this treatment indefinitely.””

https://casereports.bmj.com/content/14/10/e244195

“Cannabis oil led to lung cancer regression in 80-year-old woman: Report”

https://www.freepressjournal.in/world/cannabis-oil-led-to-lung-cancer-regression-in-80-year-old-woman-report

“Case Report: Lung Cancer Shrinks in Patient Using CBD Oil”

https://www.medscape.com/viewarticle/960949

“Daily use of cannabidiol (‘CBD’) oil may be linked to lung cancer regression”

https://www.bmj.com/company/newsroom/daily-use-of-cannabidiol-cbd-oil-may-be-linked-to-lung-cancer-regression/

Characterization of cannabinoid receptors expressed in Ewing sarcoma TC-71 and A-673 cells as potential targets for anti-cancer drug development

Life Sciences“Aims: Characterizing cannabinoid receptors (CBRs) expressed in Ewing sarcoma (EWS) cell lines as potential targets for anti-cancer drug development.

Main methods: CBR affinity and function were examined by competitive binding and G-protein activation, respectively. Cannabinoid-mediated cytotoxicity and cell viability were evaluated by LDH, and trypan blue assays, respectively.

Key findings: qRT-PCR detected CB1 (CB1R) and CB2 receptor (CB2R) mRNA in TC-71 cells. However, binding screens revealed that CBRs expressed exhibit atypical properties relative to canonical receptors, because specific binding in TC-71 could only be demonstrated by the established non-selective CB1/CB2R radioligand [3H]WIN-55,212-2, but not CB1/CB2R radioligand [3H]CP-55,940. Homologous receptor binding demonstrated that [3H]WIN-55,212-2 binds to a single site with nanomolar affinity, expressed at high density. Further support for non-canonical CBRs expression is provided by subsequent binding screens, revealing that only 9 out of 28 well-characterized cannabinoids with high affinity for canonical CB1 and/or CB2Rs were able to displace [3H]WIN-55,212-2, whereas two ligands enhanced [3H]WIN-55,212-2 binding. Five cannabinoids producing the greatest [3H]WIN-55,212-2 displacement exhibited high nanomolar affinity (Ki) for expressed receptors. G-protein modulation and adenylyl cyclase assays further indicate that these CBRs exhibit distinct signaling/functional profiles compared to canonical CBRs. Importantly, cannabinoids with the highest affinity for non-canonical CBRs reduced TC-71 viability and induced cytotoxicity in a time-dependent manner. Studies in a second EWS cell line (A-673) showed similar atypical binding properties of expressed CBRs, and cannabinoid treatment produced cytotoxicity.

Significance: Cannabinoids induce cytotoxicity in EWS cell lines via non-canonical CBRs, which might be a potential therapeutic target to treat EWS.”

https://pubmed.ncbi.nlm.nih.gov/34592231/

Cannabinoid receptors (CBRs) were detected in EWS TC-71 and A-673 cells. CBRs expressed in EWS cell lines exhibit atypical binding and signaling characteristics. Ligands with highest affinity for these non-canonical CBRs induce EWS cell death.”

https://www.sciencedirect.com/science/article/abs/pii/S0024320521009802?via%3Dihub

 

The strengths and limits of cannabinoids and their receptors in cancer: Insights into the role of tumorigenesis-underlying mechanisms and therapeutic aspects

Biomedicine & Pharmacotherapy“Cancer, as a mysterious and complex disease, has a multi-stage molecular process that uses the cellular molecular machine and multiple signaling pathways to its advantage. Cannabinoids, as terpenophenolic compounds and their derivatives, showed influences on immune system responses, inflammation, and cell growth that have sparked a growing interest in exploring their effects on cancer cell fate, as well. A large body of evidence in experimental models indicating the involvement of cannabinoids and their related receptors in cancer cell growth, development, and fate. In accordance, the present study provided insights regarding the strengths and limits of cannabinoids and their receptors in critical steps of tumorigenesis and its underlying molecular pathways such as; cancer cell proliferation, type of cell death pathway, angiogenesis, invasion, metastasis and, immune system response. Based on the results of the present study and due to the contribution of cannabinoids in various cancer cell growth control processes, these compounds cancer can be considered worthwhile in finding new alternatives for cancer therapy.”

https://pubmed.ncbi.nlm.nih.gov/34624678/

“Cannabinoids execute critical roles in multiple steps of tumorigenesis. Cannabinoids trigger apoptosis, autophagy and mitophagy in cancer cells. Cannabinoids attenuate angiogenesis; thus regulate tumor invasion. Cannabinoids and their receptors can be effective therapeutic targets in cancer pathogenesis.”

https://www.sciencedirect.com/science/article/pii/S0753332221010635?via%3Dihub

 

Cannabidiol Effectively Promoted Cell Death in Bladder Cancer and the Improved Intravesical Adhesion Drugs Delivery Strategy Could Be Better Used for Treatment

pharmaceutics-logo“Cannabidiol (CBD), a primary bioactive phytocannabinoid extracted from hemp, is reported to possess potent anti-tumorigenic activity in multiple cancers.

However, the effects of CBD on bladder cancer (BC) and the underlying molecular mechanisms are rarely reported.

Here, several experiments proved that CBD promoted BC cells (T24, 5637, and UM-UC-3) death.

In summary, this work demonstrates that CBD may become a novel reliable anticancer drug and the developed intravesical adhesion system is expected to turn into a potential means of BC chemotherapy drug delivery.

We believe that our study makes a significant contribution to the field because these results can be developed as a promising strategy for a safer and more efficient anticancer therapy.”

https://www.mdpi.com/1999-4923/13/9/1415/htm