Category Archives: Cancer

Use of Cannabis-Based Medical Products for Pediatric Health Conditions: A Systematic Review of the Recent Literature

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“Introduction: Cannabis policy is rapidly changing in the USA and across the globe, with 24 states legalizing cannabis for adult use and 38 states making medical cannabis available for those with qualified conditions. Building on prior evidence, we reviewed the recently published literature (from the past 5 years) focused on the treatment effects of naturally derived medical cannabis products within the pediatric population.

Methods: We conducted a systematic literature review of three electronic databases using MeSH terms and free-text. A study was eligible for inclusion if it investigated the efficacy of medical cannabis for any condition, it was published in 2019 or later, and the mean age of participants was under 21. We excluded studies that tested the effect of pharmaceutical cannabis-derived drug products.

Results: We identified a total of 10 studies that met our inclusion/exclusion criteria. Of the 10, 2 utilized a double-arm randomized control trial (RCT) design, 3 used a single-arm trial design, and the remaining were observational studies, a case series, or a qualitative design. Aside from autism spectrum disorder (ASD) (n = 4), studies focused on cancer, treatment-resistant epilepsy, and Sturge-Weber syndrome (SWS). Four of the five single- or double-arm trials used a CBD:THC compound in a specific ratio as treatment. Both RCTs found significant improvement in ASD-related validated measures. Other studies found general improvements in validated measures of efficacy for SWS and epilepsy. Minimal adverse events were reported.

Conclusion: In the pediatric population, emerging evidence, combined with existing literature, suggests medical cannabis may be beneficial for quality-of-life symptoms related to specific conditions, like cancer, ASD, treatment-resistant epilepsy, and SWS. More clinical trial data are necessary to establish medical cannabis as an addition to established medical guidelines.”

https://pubmed.ncbi.nlm.nih.gov/39659365/

“While more research is necessary, this review, together with other reviews of the literature , suggests that medical cannabis is potentially a viable treatment option alongside established medical treatment guidelines. This is especially true for pediatric ASD.”

https://karger.com/mca/article/7/1/257/917351/Use-of-Cannabis-Based-Medical-Products-for

Cytotoxicity of natural and synthetic cannabinoids and their synergistic antiproliferative effects with cisplatin in human ovarian cancer cells

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“Introduction: Cannabinoids are reported to suppress the growth of ovarian cancer cells, but it is unclear whether structural modifications can improve their cytotoxic effects.

Methods: Herein, an investigation into the antiproliferative effects of natural cannabinoids on human ovarian cancer Caov-3 cells identified cannabidiol (CBD) as the most promising cannabinoid. Furthermore, chemical modifications of CBD yielded a group of derivatives with enhanced cytotoxicity in Caov-3 cells.

Results: Two CBD piperazinyl derivatives (19 and 21) showed augmented antiproliferative effects with an IC50 of 5.5 and 4.1 µM, respectively, compared to CBD’s IC50 of 22.9 µM. Further studies suggest that modulation of apoptosis and ferroptosis may contribute to the cytotoxic effects of CBD and its derivatives. In addition, CBD and its derivatives (19 and 21) were explored for their potential synergistic antiproliferative effects in combination with chemotherapeutic agent cisplatin. Compounds 19 or 21 (5 µM) combined with cisplatin (1 µM) showed a synergistic effect with a combination index of 0.23 and 0.72, respectively. This effect was supported by elevated levels of reactive oxygen species in Caov-3 cells treated with cisplatin combined with 19 or 21.

Discussion: Findings from this study suggest that CBD derivatives with enhanced antiproliferative effects may exert synergistic effects with chemotherapeutic drugs, providing insight into the development of cannabinoid-based adjuvant agents for the management of ovarian cancer.”

https://pubmed.ncbi.nlm.nih.gov/39660007/

“In summary, this work supports the therapeutic potential of cannabinoids, both as standalone agents and in combination with conventional chemotherapy, for the management of ovarian cancer.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1496131/full

Cannabidiol effects in stem cells: A systematic review

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“Stem cells play a critical role in human tissue regeneration and repair. In addition, cancer stem cells (CSCs), subpopulations of cancer cells sharing similar characteristics as normal stem cells, are responsible for tumor metastasis and resistance to chemo- and radiotherapy and to tumor relapse.

Interestingly, all stem cells have cannabinoid receptors, such as cannabidiol (CBD), that perform biological functions. The aim of this systematic review was to analyze the effect of CBD on both somatic stem cells (SSCs) and CSCs.

Of the 276 articles analyzed, 38 were selected according to the inclusion and exclusion criteria. A total of 27 studied the effect of CBD on SSCs, finding that 44% focused on CBD differentiation effect and 56% on its protective activity. On the other hand, 11 articles looked at the effect of CBD on CSCs, including glioblastoma (64%), lung cancer (27%), and breast cancer (only one article).

Our results showed that CBD exerted a differentiating and protective effect on SCCs. In addition, this molecule demonstrated an antiproliferative effect on some CSCs, although most of the analyses were performed in vitro.

Therefore, although in vivo studies should be necessary to justify its clinical use, CBD and its receptors could be a specific target to act on both SSCs and CSCs.”

https://pubmed.ncbi.nlm.nih.gov/39653426/

https://iubmb.onlinelibrary.wiley.com/doi/10.1002/biof.2148

Improving the Biopharmaceutical Properties of Cannabinoids in Glioblastoma Multiforme Therapy With Nanotechnology: A Drug Delivery Perspective

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“Glioblastoma multiforme (GBM) is the most prevalent primary brain tumor in adults and is known for its rapid proliferation and infiltrative nature. Current therapeutic strategies include surgical resection followed by radio- and chemotherapy. Still, they are hindered by GBM biological characteristics and physical-chemical properties of chemotherapeutic drugs, leading to limited efficacy and poor prognosis.

Cannabinoids have emerged as potential anti-GBM agents, exhibiting antiangiogenic, antimetastatic, and antiproliferative effects. However, their hydrophobicity and poor oral bioavailability pose significant challenges for clinical applications. This study evaluates the potential of nanocarriers in enhancing the solubility and targeted delivery of cannabinoids for GBM therapy.

The innovative combination of nanotechnology with cannabinoid-based treatment offers a promising strategy to improve therapeutic outcomes. We addressed the application of nanocarriers to deliver cannabinoids, which can enhance passage across the blood-brain barrier and enable targeted therapy. Studies demonstrate the potential of nanocarriers in improving solubility, stability, and controlled release of cannabinoids, highlighting the advancements in nanocarrier design for optimized delivery to glioma cells.

Cannabinoids can exert their antitumor effect, including the induction of apoptosis through the ceramide and p8-regulated pathways and the modulation of immune responses. The evidence found in this study supports the potential of cannabinoid-based nanotechnologies in GBM therapeutic regimens as a strategy to enhance its efficacy and patient outcomes.”

https://pubmed.ncbi.nlm.nih.gov/39620407/

https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/10.1002/ddr.70023

Cannabidiol mitigates methotrexate-induced hepatic injury via SIRT-1/p53 signaling and mitochondrial pathways: reduces oxidative stress and inflammation

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“Methotrexate (MTX), a widely used chemotherapeutic agent, often induces hepatotoxicity, limiting its clinical utility.

Cannabidiol (CBD), derived from hemp, possesses antioxidant, anti-inflammatory, and antiapoptotic properties.

This study aims to investigate CBD’s protective effects against MTX-induced liver injury and elucidate the underlying mechanisms.

Thirty-two female Wistar Albino rats were divided into four groups: control, MTX (20 mg/kg intraperitoneally [i.p.] once), MTX+CBD (20 mg/kg i.p. once + 5 mg/kg i.p. for seven days), and CBD (5 mg/kg, i.p. for seven days). Biochemical analyses of serum and liver tissues were performed to assess oxidative stress markers (total oxidant status, total antioxidant status, oxidative stress index), liver function tests (AST, ALT), and antioxidant enzyme activities (glutathione peroxidase, superoxide dismutase). Histopathological and immunohistochemical examinations were conducted to evaluate liver tissue damage and TNF-α expression. Genetic analyses were performed to measure the expression levels of SIRT-1, p53, Bcl-2, and Bax genes using RT-qPCR. MTX administration increased oxidative stress markers, liver enzymes, TNF-α, p53, and Bax levels while decreasing antioxidant defenses and SIRT-1 expression.

CBD administration reversed these alterations effectively.

CBD mitigated MTX-induced hepatotoxicity by reducing oxidative stress, inflammation, and apoptosis. It activates antioxidant defenses via SIRT-1 upregulation, suppresses inflammation by reducing TNF-α, and prevents apoptosis by modulating p53, Bcl-2, and Bax gene expressions.

These findings suggest CBD could be a promising therapeutic agent for chemotherapy-induced liver damage. Further research is warranted to explore additional pathways and broader molecular mechanisms.”

https://pubmed.ncbi.nlm.nih.gov/39603835/

https://www.tandfonline.com/doi/full/10.1080/01480545.2024.2425994


Discovery of Ring-Annulated Analogues of Cannabidiol as Potential Anticancer Agents: Synthesis and Biological Evaluation

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“Cannabidiol (CBD) is a nonpsychoactive cannabinoid derived from Cannabis sativa and its potential therapeutic effects extend beyond its well-known antiepileptic properties. Exploring CBD and its analogues as anticancer agents has gained significant attention in recent years.

In this study, a series of novel ring-annulated analogues of CBD with oxazinyl moiety were synthesized and evaluated for their antiproliferative effect.

The analogues 4d and 4h demonstrate promising activity against breast and colorectal cancer. Furthermore, mechanistic insights revealed that the identified candidates arrest the G1 phase of the cell cycle and induce apoptosis via the mitochondrial pathway in breast cancer cell lines.

Notably, CBD ring-annulated analogues 4d or 4h exhibit enhanced solubility, better metabolic stability, and lowered cytochrome P450 (CYP) inhibition liability compared to CBD.

These multifaceted attributes highlight the potential of cannabinoid-based candidates for further preclinical development.”

https://pubmed.ncbi.nlm.nih.gov/39563806/

https://pubs.acs.org/doi/10.1021/acsmedchemlett.4c00233

Combinatorial effects of cannabinoid receptor 1 and 2 agonists on characteristics and proteomic alteration in MDA-MB-231 breast cancer cells

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“Breast cancer is the most common cancer diagnosed in women worldwide. However, the effective treatment for breast cancer progression is still being sought.

The activation of cannabinoid receptor (CB) has been shown to negatively affect breast cancer cell survival.

Our previous study also reported that breast cancer cells responded to various combinations of CB1 and CB2 agonists differently. Nonetheless, the mechanism underlying this effect and whether this phenomenon can be seen in other cancer characteristics remain unknown. Therefore, this study aims to further elucidate the effects of highly selective CB agonists and their combination on triple-negative breast cancer proliferation, cell cycle progression, invasion, lamellipodia formation as well as proteomic profile of MDA-MB-231 breast cancer cells.

The presence of CB agonists, specifically a 2:1 (ACEA: GW405833) combination, prominently inhibited colony formation and induced the S-phase cell cycle arrest in MDA-MB-231 cells. Furthermore, cell invasion ability and lamellipodia formation of MDA-MB-231 were also attenuated by the exposure of CB agonists and their 2:1 combination ratio. Our proteomic analysis revealed proteomic profile alteration in MDA-MB-231 upon CB exposure that potentially led to breast cancer suppression, such as ZPR1/SHC1/MAPK-mediated cell proliferation and AXL/VAV2/RAC1-mediated cell motility pathways.

Our findings showed that selective CB agonists and their combination suppressed breast cancer characteristics in MDA-MB-231 cells. The exposure of CB agonists also altered the proteomic profile of MDA-MB-231, which could lead to cell proliferation and motility suppression.”

https://pubmed.ncbi.nlm.nih.gov/39527598/

“Our study demonstrated that the presence of CB agonists hindered breast cancer cell growth, cell cycle progression, invasion through extracellular matrices and lamellipodia formation. The exposure of specific combination of CB1 and CB2 agonists also enhanced their breast cancer suppression effects. Moreover, breast cancer survival and motility-related proteins affected by the presence of these agonists suggesting the potential pathways underlying their effects were also depicted in this study.”

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0312851

Cannabidiol (CBD) Protects Lung Endothelial Cells from Irradiation-Induced Oxidative Stress and Inflammation In Vitro and In Vivo

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“Objective: Radiotherapy, which is commonly used for the local control of thoracic cancers, also induces chronic inflammatory responses in the microvasculature of surrounding normal tissues such as the lung and heart that contribute to fatal radiation-induced lung diseases (RILDs) such as pneumonitis and fibrosis. In this study, we investigated the potential of cannabidiol (CBD) to attenuate the irradiation damage to the vasculature. 

Methods: We investigated the ability of CBD to protect a murine endothelial cell (EC) line (H5V) and primary lung ECs isolated from C57BL/6 mice from irradiation-induced damage in vitro and lung ECs (luECs) in vivo, by measuring the induction of oxidative stress, DNA damage, apoptosis (in vitro), and induction of inflammatory and pro-angiogenic markers (in vivo). 

Results: We demonstrated that a non-lethal dose of CBD reduces the irradiation-induced oxidative stress and early apoptosis of lung ECs by upregulating the expression of the cytoprotective mediator heme-oxygenase-1 (HO-1). The radiation-induced increased expression of inflammatory (ICAM-2, MCAM) and pro-angiogenic (VE-cadherin, Endoglin) markers was significantly reduced by a continuous daily treatment of C57BL/6 mice with CBD (i.p. 20 mg/kg body weight), 2 weeks before and 2 weeks after a partial irradiation of the lung (less than 20% of the lung volume) with 16 Gy. 

Conclusions: CBD has the potential to improve the clinical outcome of radiotherapy by reducing toxic side effects on the microvasculature of the lung.”

https://pubmed.ncbi.nlm.nih.gov/39518030/

“In this study, we demonstrate that cannabidiol (CBD), the non-psychogenic component of cannabis, mediates anti-inflammatory and anti-oxidative effects that protect the microvasculature of the lung against radiation-induced damage using in vitro and in vivo murine models. CBD therefore has the potential to improve the clinical outcome of radiotherapy by reducing normal tissue toxicity in the lung.”

https://www.mdpi.com/2072-6694/16/21/3589

Cannabidiol and fluorinated derivative anti-cancer properties against glioblastoma multiforme cell lines, and synergy with imidazotetrazine agents

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“Background: Glioblastoma multiforme (GBM) is an aggressive cancer with poor prognosis, partly due to resistance to the standard chemotherapy treatment, temozolomide (TMZ). Phytocannabinoid cannabidiol (CBD) has exhibited anti-cancer effects against GBM, however, CBD’s ability to overcome common resistance mechanisms to TMZ have not yet been investigated. 4′-Fluoro-cannabidiol (4′-F-CBD, or HUF-101/PECS-101) is a derivative of CBD, that exhibits increased activity compared to CBD during in vivo behavioural studies.

Methods: This anti-cancer activity of cannabinoids against GBM cells sensitive to and representing major resistance mechanisms to TMZ was investigated. Cannabinoids were also studied in combination with imidazotetrazine agents, and advanced mass spectrometry with the 3D OrbiSIMS was used to investigate the mechanism of action of CBD.

Results: CBD and 4′-F-CBD were found to overcome two major resistance mechanisms (methylguanine DNA-methyltransferase (MGMT) overexpression and DNA mismatch repair (MMR)-deficiency). Synergistic responses were observed when cells were exposed to cannabinoids and imidazotetrazine agents. Synergy increased with T25 and 4′-F-CBD. 3D OrbiSIMS analysis highlighted the presence of methylated-DNA, a previously unknown anti-cancer mechanism of action of CBD.

Conclusions: This work demonstrates the anti-cancer activity of 4′-F-CBD and the synergy of cannabinoids with imidazotetrazine agents for the first time and expands understanding of CBD mechanism of action.”

https://pubmed.ncbi.nlm.nih.gov/39516685/

https://www.nature.com/articles/s44276-024-00088-0

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/