Cannabidiol Combination Enhances Photodynamic Therapy Effects on MCF-7 Breast Cancer Cells

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“Cannabis sativa is a well-known plant for its psychoactive effects; however, its many derivatives, such as Cannabidiol (CBD), contain several therapeutic applications. Tetrahydrocannabinol (THC) is the main cannabis derivative responsible for psychoactive properties, while CBD is non-psychotropic. For this reason, CBD has been more exploited in the last decade.

CBD has been connected to multiple anticancer properties, and when combined with photodynamic therapy (PDT), it is possible to eradicate tumors more effectively. In this study, CBD was utilized to treat MCF-7 breast cancer cells, followed by in vitro PDT combination therapy. Conventional breast cancer treatment modalities such as chemotherapy, radiotherapy, etc. have been reported for inducing a number of undesirable side effects, recurrence of the disease, and low quality of life.

In this study, cells were exposed to varying concentrations of CBD (i.e., 1.25, 2.5, 5, 10, and 20 μg/mL) and incubated 12 and 24 h after treatment. The optimal doses were then used in combination therapy. Morphology and biochemical assays, including lactate dehydrogenase (LDH) for membrane integrity, adenosine triphosphate (ATP) for viability, and trypan blue exclusion assay for viability, were used to examine cellular responses after treatments. The optimal concentration was then utilized in Hypericin-Gold nanoparticles mediated PDT combination.

The results revealed that, in a dose-dependent manner, conventional morphological characteristics of cell death, such as vacuolization, blebbing, and floating were observed in treated cells. The biochemical responses demonstrated an increase in LDH, a decrease in ATP, and a reduction in viability. This study demonstrated that CBD induces cell death in MCF-7 breast cancer cells cultured in vitro. The immunofluorescence results of combination therapy indicated that cell death occurred via apoptosis.

In conclusion, this study proposes that the CBD and PDT combination therapy is effective in killing MCF-7 breast cancer cells in vitro by induction of apoptosis.”

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.”

Engineering cannabidiol synergistic carbon monoxide nanocomplexes to enhance cancer therapy via excessive autophagy

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“Although carbon monoxide (CO)-based treatments have demonstrated the high cancer efficacy by promoting mitochondrial damage and core-region penetrating ability, the efficiency was often compromised by protective autophagy (mitophagy). Herein, cannabidiol (CBD) is integrated into biomimetic carbon monoxide nanocomplexes (HMPOC@M) to address this issue by inducing excessive autophagy. The biomimetic membrane not only prevents premature drugs leakage, but also prolongs blood circulation for tumor enrichment. After entering the acidic tumor microenvironment, carbon monoxide (CO) donors are stimulated by hydrogen oxide (H2O2) to disintegrate into CO and Mn2+. The comprehensive effect of CO/Mn2+ and CBD can induce ROS-mediated cell apoptosis. In addition, HMPOC@M-mediated excessive autophagy can promote cancer cell death by increasing autophagic flux via class III PI3K/BECN1 complex activation and blocking autolysosome degradation via LAMP1 downregulation. Furthermore, in vivo experiments showed that HMPOC@M+ laser strongly inhibited tumor growth and attenuated liver and lung metastases by downregulating VEGF and MMP9 proteins. This strategy may highlight the pro-death role of excessive autophagy in TNBC treatment, providing a novel yet versatile avenue to enhance the efficacy of CO treatments. Importantly, this work also indicated the applicability of CBD for triple-negative breast cancer (TNBC) therapy through excessive autophagy.”

“In our points, this comprehensive strategy will open a new door for efficient triple-negative breast cancer therapy through CBD-induced excessive autophagy.”

Cannabinol inhibits cell growth and triggers cell cycle arrest and apoptosis in cancer cells

Biocatalysis and Agricultural Biotechnology

“Cancer is one of the most difficult diseases to treat and cure.”

“Cannabinol (CBN), one of the active ingredients from the cannabis plant, is the breakdown molecule of Δ9-tetrahydrocannabinol (Δ9-THC) which is the most abundant psychoactive cannabinoid.”

“Cannabinol (CBN) is a weak-psychoactive cannabinoid and has been shown to exert several bio-logical activities. At the same time, not much is known about the anti-cancer activities of CBN. In this report, we characterized the anti-tumor effects of CBN on the glioma A172, liver cancer HepG2 and breast cancer HCC1806 cell lines.

We found that CBN reduces the proliferation of the analyzed cancer cells and modulates the level of cannabinoid receptors, including GPR18, CB2 and GPR55. Furthermore, CBN inhibits the ERK1/2 pathway in A172 and HepG2 cells, while suppressing the AKT pathway in HCC1086 cells. Moreover, CBN may cause apoptosis through downregulation of p21 and p27 as well as a cell cycle arrest at G1 or S-phase via decreasing the CDK1, CDK2, and cyclin E1 levels.

Taken together, these results offer new insights into the anti-cancer properties of CBN.”

“CBN, one of the weak-psychoactive cannabinoids, have demonstrated various medicinal properties, including anti-inflammatory, antibacterial, analgesic and even anti-tumor.”

“In this study, we revealed the antitumor activity of CBN in three different tumor cell lines, glioma A172, liver cancer HepG2 and breast cancer HCC1806 cell lines. We report that cannabinol inhibits proliferation of several cancer cell lines by regulation of the signaling pathways involving ERK and AKT as well as by altering the expression of cannabinoid receptors. Moreover, we also found that CBN induces apoptosis and cell cycle arrest and partially uncovered underlying molecular mechanisms. Our findings provide novel information about the anti-cancer properties of CBN and justify further research to investigate the role of CBN as cancer therapeutic.”

Cannabidiol Antiproliferative Effect in Triple-Negative Breast Cancer MDA-MB-231 Cells Is Modulated by Its Physical State and by IGF-1

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“Cannabidiol (CBD) is a non-psychoactive phytocannabinoid that has been discussed for its safety and efficacy in cancer treatments. For this reason, we have inquired into its use on triple-negative human breast cancer. Analyzing the biological effects of CBD on MDA-MB-231, we have demonstrated that both CBD dosage and serum concentrations in the culture medium influence its outcomes; furthermore, light scattering studies demonstrated that serum impacts the CBD aggregation state by acting as a surfactant agent. Pharmacological studies on CBD in combination with chemotherapeutic agents reveal that CBD possesses a protective action against the cytotoxic effect exerted by cisplatin on MDA-MB-231 grown in standard conditions. Furthermore, in a low serum condition (0.5%), starting from a threshold concentration (5 µM), CBD forms aggregates, exerts cytostatic antiproliferative outcomes, and promotes cell cycle arrest activating autophagy. At doses above the threshold, CBD exerts a highly cytotoxic effect inducing bubbling cell death. Finally, IGF-1 and EGF antagonize the antiproliferative effect of CBD protecting cells from harmful consequences of CBD aggregates. In conclusion, CBD effect is strongly associated with the physical state and concentration that reaches the treated cells, parameters not taken into account in most of the research papers.”

“Among the various biological properties of phytocannabinoids, their ability to induce antiproliferative effects in different human cancer cells raises the scientific interest in their therapeutic potential in the field of oncology.”

Cannabinoids in Breast Cancer: Differential Susceptibility According to Subtype

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“Although cannabinoids have been used for centuries for diverse pathological conditions, recently, their clinical interest and application have emerged due to their diverse pharmacological properties. Indeed, it is well established that cannabinoids exert important actions on multiple sclerosis, epilepsy and pain relief.

Regarding cancer, cannabinoids were first introduced to manage chemotherapy-related side effects, though several studies demonstrated that they could modulate the proliferation and death of different cancer cells, as well as angiogenesis, making them attractive agents for cancer treatment.

In relation to breast cancer, it has been suggested that estrogen receptor-negative (ER) cells are more sensitive to cannabinoids than estrogen receptor-positive (ER+) cells. In fact, most of the studies regarding their effects on breast tumors have been conducted on triple-negative breast cancer (TNBC). Nonetheless, the number of studies on human epidermal growth factor receptor 2-positive (HER2+) and ER+ breast tumors has been rising in recent years. However, besides the optimistic results obtained thus far, there is still a long way to go to fully understand the role of these molecules. This review intends to help clarify the clinical potential of cannabinoids for each breast cancer subtype.”

“Cannabinoids have been used for centuries in several therapeutic applications. Regarding cancer, the use of cannabinoids has already been approved in several countries for the relief of chemotherapy-associated effects, but their clinical potential is greater than initially thought, and their clinical interest has been rising in recent years. Pre-clinical studies have demonstrated that cannabinoids exert important antitumor properties in the main breast cancer subtypes, particularly in TNBC, where different phytocannabinoids and synthetic cannabinoids have shown interesting therapeutic actions.”

“Thus, it is strongly believed that Cannabis, being an important natural source of many cannabinoids, may be a potential therapeutic option for the treatment or modulation of different physiological processes and, even, pathological conditions, such as cancer.”

“Experimental evidence accumulated during the last decade supports that cannabinoids, the active components of Cannabis sativa and their derivatives, possess anticancer activity. Thus, these compounds exert anti-proliferative, pro-apoptotic, anti-migratory and anti-invasive actions in a wide spectrum of cancer cells in culture. Moreover, tumor growth, angiogenesis and metastasis are hampered by cannabinoids in xenograft-based and genetically-engineered mouse models of cancer. This review summarizes our current knowledge on the anti-tumor potential of cannabinoids in breast cancer, which suggests that cannabinoid-based medicines may be useful for the treatment of most breast tumor subtypes.”

Cannabis Use Patterns among Patients with Early-Stage Breast Cancer in a Large Multicenter Cohort from a State with Legalized Adult Non-Medical Cannabis

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“Purpose/objective(s): Cannabis use among patients with cancer is an area of great interest given its widespread acceptance despite the lack of supporting clinical data. The absence of data limits the understanding of potential clinical benefits of cannabis and the ability of providers to deliver evidence-based recommendations for patient care. We explored cannabis use patterns in patients with early-stage breast cancer in a large multicenter cohort in a state with legalized adult non-medical cannabis.

Materials/methods: Initial questions about cannabis use history and frequency were introduced in Michigan Radiation Oncology Quality Consortium (MROQC) breast cancer patient surveys on 2/1/2020 for female patients receiving radiation after lumpectomy for non-metastatic breast cancer. Expanded questions were introduced on 6/28/2022 to assess mode of administration, active ingredient, and reason for use. Summary statistics were generated. A multivariable model using logistic regression identified patient characteristics associated with cannabis use.

Results: Among 3948 eligible patients, 2738 (69.35%) completed survey questions, and 2462/2738 (89.9%) completed the initial question on cannabis use. Among those, 364/2462 (14.8%) noted cannabis use in the last 30 days, 588 (23.9%) noted remote use (>30 days ago), 1462 (59.4%) reported never having used cannabis, 44 (1.8%) preferred not to answer cannabis use questions, and 4 (0.4%) did not provide use history. Younger age [age <50 vs 60-70, OR 2.5 (95% CI 1.65, 3.79) p<0.001)], Hispanic ethnicity [OR 2.20 (95% CI 1.06, 4.56) p = 0.03], history of smoking [OR 2.56 (95% CI 1.88, 3.48) p<0.001], current smoking [OR 4.70 (95% CI 3.22, 6.86) p<0.001)], and prior chemotherapy [OR 1.40 (95% CI 1.00, 1.96) p = 0.05] predicted recent cannabis use in a multivariable model. Of the 364 patients endorsing cannabis use in the last 30 days, 89 (24.5%), 72 (19.8%), 29 (8.0%), 66 (18.1%), 30 (8.2%), and 78 (21.4%) reported using cannabis 1-2 days, 3-5 days, 6-9 days, 10-19 days, 20-29 days, and all 30 days, respectively. The most common modes of administration among 76 individuals who responded to the expanded questionnaire to date were oral (39.4%), smoking (30.3%), and topical (10.5%). The products used contained tetrahydrocannabinol (THC; 26.3%), cannabidiol (CBD; 19.7%), balanced levels of THC and CBD (19.7%), or active ingredients that were unknown to the patient (34.2%). Patients frequently endorsed cannabis use for insomnia, anxiety, and pain.

Conclusion: Many patients with early-stage breast cancer are using cannabis. Younger age, Hispanic ethnicity, smoking, and chemotherapy history are predictors of cannabis use. Patients are often unaware of the active ingredients in the products that they use, suggesting an important role for patient education and a need to equip providers to advise patients in their care.”

CBD Inhibits In Vivo Development of Human Breast Cancer Tumors

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“Inflammation is a critical component of cancer development. Previously, we showed in vitro that IL-1β treatment of non-invasive human breast cancer MCF-7 cells promoted their transition to a malignant phenotype (6D cells). This epithelial-mesenchymal transition was reverted by exposure to cannabidiol (CBD).

We show in a murine model that subcutaneous inoculation of 6D cells induced formation and development of tumors, the cells of which keep traits of malignancy. These processes were interrupted by administration of CBD under two schemes: therapeutic and prophylactic. In the therapeutic scheme, 6D cells inoculated mice developed tumors that reached a mean volume of 540 mm3 at 45 days, while 50% of CBD-treated mice showed gradual resorption of tumors. In the prophylactic scheme, mice were pre-treated for 15 days with CBD before cells inoculation. The tumors formed remained small and were eliminated under continuous CBD treatment in 66% of the animals. Histological and molecular characterization of tumors, from both schemes, revealed that CBD-treated cells decreased the expression of malignancy markers and show traits related with apoptosis.

These results confirm that in vivo CBD blocks development of breast cancer tumors formed by cells induced to malignancy by IL-1β, endorsing its therapeutic potential for cancer treatment.”

“In conclusion, the present study shows that CBD, properly administered, can effectively block development of human breast cancer tumors in vivo, without causing adverse effects, by regulating in the tumor cells the expression of malignant traits and bearing characteristics of a possible route via apoptosis, both favorable attributes for an anticancer drug.”

Rimonabant and Cannabidiol Rewrite the Interactions between Breast Cancer Cells and Tumor Microenvironment

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“The spread of breast cancer to distant sites is the major cause of death in breast cancer patients. Increasing evidence supports the role of the tumor microenvironment (TME) in breast cancers, and its pathologic assessment has become a diagnostic and therapeutic tool. In the TME, a bidirectional interplay between tumor and stromal cells occurs, both at the primary and metastatic site. Hundreds of molecules, including cytokines, chemokines, and growth factors, contribute to this fine interaction to promote tumor spreading.

Here, we investigated the effects of Rimonabant and Cannabidiol, known for their antitumor activity, on reprogramming the breast TME.

Both compounds directly affect the activity of several pathways involved in breast cancer progression. To mimic tumor-stroma interactions during breast-to-lung metastasis, we investigated the effect of the compounds on growth factor secretion from metastatic breast cancer cells and normal and activated lung fibroblasts.

In this setting, we demonstrated the anti-metastatic potential of the two compounds, and the membrane array analyses highlighted their ability to alter the release of factors involved in the autocrine and paracrine regulation of tumor proliferation, angiogenesis, and immune reprogramming.

The results enforce the antitumor potential of Rimonabant and Cannabidiol, providing a novel potential tool for breast cancer TME management.”

Cannabinoids and standardized cannabis extracts inhibit migration, invasion, and induce apoptosis in MCF-7 cells through FAK/MAPK/Akt/NF-κB signaling

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“Background: Breast cancer is the highest incidence of all types of cancer in women, and the cancer metastasis process accounts for a majority of cancer deaths. Two major cannabinoids, Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), from Cannabis sativa are expected to have anti-cancer activity. This study aimed to investigate the effects of THC, CBD, and standardized cannabis extracts (F1, F2, and F3) on migration, invasion, and apoptosis of human breast cancer (MCF-7) cells.

Methods: Cell viability, survival, and apoptosis were determined using the MTT, clonogenic, and nuclear staining assays, respectively, while cancer cell migration and invasion were evaluated by the wound healing, trans-well, and filopodia assays. Western blot analysis was used to find out the mechanisms of the cannabinoids against MCF-7 cells.

Results: CBD, THC, and F1 inhibited filopodia formation, migration, and invasion of MCF-7 cells through suppressing the expression of the FAK, Akt, ERK1/2, p38MAPKs, and NF-κB upstream pathways, as well as inhibiting the Rac1/Cdc42 downstream pathways. In addition, CBD significantly inhibited the mTOR pathway. Furthermore, CBD and F1 induced apoptosis in MCF-7 cells via the Bcl-2/caspase-3 pathways.

Conclusion: These results indicate that THC, CBD, and F1 have great abilities for preventing breast cancer cell metastasis in in vitro experiments.”