“The calcium-selective oncochannel TRPV6 is an important driver of cell proliferation in human cancers. Despite increasing interest of pharmacological research in developing synthetic inhibitors of TRPV6, natural compounds acting at this channel have been largely neglected. On the other hand, pharmacokinetics of natural small-molecule antagonists optimized by nature throughout evolution endows these compounds with a medicinal potential to serve as potent and safe next-generation anti-cancer drugs. Here we report the structure of human TRPV6 in complex with tetrahydrocannabivarin (THCV), a natural cannabinoid inhibitor extracted from Cannabis sativa. We use cryo-electron microscopy combined with electrophysiology, calcium imaging, mutagenesis, and molecular dynamics simulations to identify THCV binding sites in the portals that connect the membrane environment surrounding the protein to the central cavity of the channel pore and to characterize the allosteric mechanism of TRPV6 inhibition. We also propose the molecular pathway taken by THCV to reach its binding site. Our study provides a foundation for the development of new TRPV6-targeting drugs.”
“It is known that gynecological cancers remain a worldwide problem and as shown by the statistics, there is a need for new gynecological cancer treatments. Cannabinoids, the pharmacologically active compounds of the Cannabis sativa plant, have been used for many centuries by individuals as a symptomatic treatment to alleviate pain, nausea, vomiting, and to help stimulate appetite. Research has revealed that cannabinoids also exert anti-cancer activity such as anti-proliferative and pro-apoptotic effects through a variety of mechanisms. There is significant value in the development of these compounds as anti-cancer therapies in clinical practice as they do not produce the typical toxic side effects that exist with conventional therapies and recent clinical trials have shown their great tolerability by patients at high doses. Cannabinoids can induce psychoactive effects that could limit their progression. Therefore, non-psychoactive cannabinoids are attracting pharmacological interest due to their inability to produce psychological effects. Recent studies have focussed on non-psychoactive cannabinoids in ovarian cancer and have revealed promising pre-clinical results that indicate that these compounds may have potential benefits in the treatment of these cancers. However, there are still unanswered questions and research gaps that need to be addressed. This review summarizes the current understanding of this topic and identifies the current gaps in knowledge that provide a useful direction for future work.”
“Cannabis enjoyed a “golden age” as a medicinal product in the late 19th, early 20th century, but the increased risk of overdose and abuse led to its criminalization. However, the 21st century have witnessed a resurgence of interest and a large body of literature regarding the benefits of cannabinoids have emerged. As legalization and decriminalization have spread around the world, cancer patients are increasingly interested in the potential utility of cannabinoids. Although eager to discuss cannabis use with their oncologist, patients often find them to be reluctant, mainly because clinicians are still not convinced by the existing evidence-based data to guide their treatment plans. Physicians should prescribe cannabis only if a careful explanation can be provided and follow up response evaluation ensured, making it mandatory for them to be up to date with the positive and also negative aspects of the cannabis in the case of cancer patients. Consequently, this article aims to bring some clarifications to clinicians regarding the sometimes-confusing various nomenclature under which this plant is mentioned, current legislation and the existing evidence (both preclinical and clinical) for the utility of cannabinoids in cancer patients, for either palliation of the associated symptoms or even the potential antitumor effects that cannabinoids may have.”
“Over the past decades, Colombia has suffered complex social problems related to illicit crops, including forced displacement, violence, and environmental damage, among other consequences for vulnerable populations. Considerable effort has been made in the regulation of illicit crops, predominantly Cannabis sativa, leading to advances such as the legalization of medical cannabis and its derivatives, the improvement of crops, and leaving an open window to the development of scientific knowledge to explore alternative uses. It is estimated that C. sativa can produce approximately 750 specialized secondary metabolites. Some of the most relevant due to their anticancer properties, besides cannabinoids, are monoterpenes, sesquiterpenoids, triterpenoids, essential oils, flavonoids, and phenolic compounds. However, despite the increase in scientific research on the subject, it is necessary to study the primary and secondary metabolism of the plant and to identify key pathways that explore its great metabolic potential. For this purpose, a genome-scale metabolic reconstruction of C. sativa is described and contextualized using LC-QTOF-MS metabolic data obtained from the leaf extract from plants grown in the region of Pesca-Boyaca, Colombia under greenhouse conditions at the Clever Leaves facility. A compartmentalized model with 2101 reactions and 1314 metabolites highlights pathways associated with fatty acid biosynthesis, steroids, and amino acids, along with the metabolism of purine, pyrimidine, glucose, starch, and sucrose. Key metabolites were identified through metabolomic data, such as neurine, cannabisativine, cannflavin A, palmitoleic acid, cannabinoids, geranylhydroquinone, and steroids. They were analyzed and integrated into the reconstruction, and their potential applications are discussed. Cytotoxicity assays revealed high anticancer activity against gastric adenocarcinoma (AGS), melanoma cells (A375), and lung carcinoma cells (A549), combined with negligible impact against healthy human skin cells.”
“There have been significant advances in the treatment of cancer in the past decade. However, patients continue to suffer from significant side effects of antineoplastic agents that greatly affect their quality of life (QOL), including chemotherapy-induced nausea and vomiting (CINV), chemotherapy-induced peripheral neuropathy (CIPN), and chemotherapy-induced alopecia (CIA). This review aims to provide an updated overview of emerging strategies for the management and prevention of these immediate and long-lasting side effects. The use of integrative medicine including cannabis continues to evolve in the realm of CINV and cancer-related anorexia. Although no pharmaceutical agent has been approved for the prevention of CIPN, cryotherapy, compression therapy and, more recently, cryocompression therapy have shown benefit in small trials, but there are concerns with tolerability especially related to cryotherapy. More data are necessary to determine an effective and tolerable option to prevent CIPN in large, randomized studies. Scalp cooling (SC), which has a similar mechanism to cryotherapy and compression therapy for CIPN prevention, has proven to be an effective and tolerable approach in randomized studies and has significantly limited CIA, an entity that definitively affects the QOL of patients living with cancer. Taken together, cannabis, cryotherapy, compression and cryocompression therapy, and SC all strive to improve the QOL of patients living with cancer by minimizing the side effects of chemotherapeutic agents.”
“Non-melanoma skin cancer is one of the most common malignancies reported around the globe. Current treatment therapies fail to meet the desired therapeutic efficacy due to high degree of drug resistance. Thus, there is prominent demand in advancing the current conventional therapy to achieve desired therapeutic efficacy. To break the bottleneck, nanoparticles have been used as next generation vehicles that facilitate the efficient interaction with the cancer cells. Here, we developed combined therapy of 5-fluorouracil (5-FU) and cannabidiol (CBD)-loaded nanostructured lipid carrier gel (FU-CBD-NLCs gel). The current investigation has been designed to evaluate the safety and efficacy of developed 5-Flurouracil and cannabidiol loaded combinatorial lipid-based nanocarrier (FU-CBD NLCs) gel for the effective treatment of skin cancer. Initially, confocal microscopy study results showed excellent uptake and deposition at epidermal and the dermal layer. Irritation studies performed by IR camera and HET cam shows FU-CBD NLCs was much more tolerated and less irritant compared to conventional treatment. Furthermore, gamma scintigraphy evaluation shows the skin retention behavior of the formulation. Later, in-ovo tumor remission studies were performed, and it was found that prepared FU-CBD NLCs was able to reduce tumor volume significantly compared to conventional formulation. Thus, obtained results disclosed that permeation and disposition of 5-FU and CBD into different layers of the skin FU-CBD NLCs gel could be more potential carrier than conventional gel. Furthermore, prepared formulation showed greater tumor remission, better survival rate, reduction in tumor number, area, and volume with improved biochemical profile. Thus, prepared gel could serve as a promising formulation approach for the skin cancer treatment.”
“Aging is usually considered a key risk factor associated with multiple diseases, such as neurodegenerative diseases, cardiovascular diseases and cancer. Furthermore, the burden of age-related diseases has become a global challenge. It is of great significance to search for drugs to extend lifespan and healthspan. Cannabidiol (CBD), a natural nontoxic phytocannabinoid, has been regarded as a potential candidate drug for antiaging. An increasing number of studies have suggested that CBD could benefit healthy longevity. Herein, we summarized the effect of CBD on aging and analyzed the possible mechanism. All these conclusions may provide a perspective for further study of CBD on aging.”
“CBD is a potential antiaging candidate. CBD possesses antioxidant, anti-inflammatory and autophagy-inducing properties. CBD has potentially beneficial therapeutic effects for several age-related diseases.”
“Cannabinoids are compounds found in the cannabis sativa plant. Cannabinoids, such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), have potential therapeutic benefits in various medical conditions. Some can activate the cannabinoid receptors type-1 and -2 (CB1 and CB2), that are part of the endocannabinoid system (ECS), alongside the endocannabinoids and their metabolic enzymes.
The ECS regulates physiological and cognitive processes and is a potential therapeutic target for a wide range of health conditions like chronic pain, anxiety, and neurodegenerative diseases. Synthetic cannabinoids, are associated with serious health risks, including addiction, psychosis, and death. Nonetheless, some of these molecules are also being explored for pharmacological applications.
Angiogenesis is the process of forming new blood vessels from existing ones, crucial for growth, repair, and tissue maintenance. Dysregulation of this process is associated with several diseases, including cancer, diabetic retinopathy and reproductive pathologies, such as preeclampsia. Recent data suggests that cannabinoids may affect angiogenesis.
Here, we reviewed their impact on pro-angiogenic factors, extracellular matrix enzymes and inhibitors, immune-inflammatory responses, angiogenic pathways and functional assays, focusing on the main compounds for each cannabinoid class: THC and CBD for phytocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG) for endocannabinoids and WIN-55, JWH-133, XLR-11, LYR-7 and LYR-8, for the synthetic cannabinoids.
Despite conflicting reports about the actions of phytocannabinoids and endocannabinoids on angiogenesis, the ability to modulate the angiogenic process is undoubtedly confirmed. This may open a new therapeutical route for angiogenesis-related pathologies. In addition, synthetic cannabinoids present anti-angiogenic actions in several cell models, hinting their potential as anti-angiogenic drugs.”
“Introduction: Taste alteration is a common adverse effect of chemotherapy. This study aimed to investigate the effect of cannabidiol (CBD) on Lean Body Mass (LBM), and taste alterations during oxaliplatin- or paclitaxel-based chemotherapy.
Methods: LBM was estimated by bioelectrical impedance analysis (BIA), and taste perception was evaluated by a randomized sensory test of six samples: sweet, salt, and umami, all in weak and strong concentrations. Taste perceptions were scored on visual analog scales. Patients in the intervention group received oral CBD 300 mg/day for 8 days; patients in the control group did not. Patients were followed for three cycles of chemotherapy.
Results: Twenty-two/ten patients (intervention/control group) were eligible. No effects on LBM were demonstrated. At baseline, the control group was able to differentiate between weak and strong saltiness and weak and strong sweetness but lost this ability after three cycles of chemotherapy. At baseline, the intervention group was unable to differentiate between the concentrations but gained the ability to significantly differentiate between weak and strong sweetness (p = 0.03) and weak and strong saltiness (p = 0.04) after three cycles of chemotherapy and treatment with CBD.
Conclusions: CBD may improve patients’ ability to differentiate taste strengths during chemotherapy.”
“Background: Targeting protein kinase B (Akt) and its downstream signaling proteins are promising options in designing novel and potent drug candidates against hepatocellular carcinoma (HCC). The present study explores the anti-HCC potentials of Cannabis sativa (C. sativa) extract via the involvement of Akt using both in silico and in vivo animal models of HCC approaches.
Methods: Phytoconstituents of C. sativa extract obtained from Gas Chromatography Mass-spectrometry (GCSM) were docked into the catalytic domain of Akt-2. The Diethylnitrosamine (DEN) model of HCC was treated with C. sativa extract. The effects of C. sativa extract treatments on DEN model of hepatocellular carcinoma were assessed by One-way analysis of variance (ANOVA) of the treated and untreated groups RESULT: The lead phytoconstituents of C. sativa extract, Δ-9-tetrahydrocannabinol (Δ-9-THC) and cannabidiol form stable hydrophobic and hydrogen bond interactions within the catalytic domain of Akt-2. C. sativa extract (15 mg/kg and 30 mg/kg) respectively gives a 3-fold decrease in the activities of liver function enzymes when compared with the positive control (group 2). It also gives a 1.5-fold decrease in hepatic lipid peroxidation and elevates serum antioxidant enzymes’ activities by 1-fold in HCC treated Wistar rats when compared with the positive control (group 2). In an animal model of hepatocellular carcinoma, C. sativa extract significantly downregulated Akt and HIF mRNAs in groups 3, 4, and 5 with 2, 1.5, 2.5-fold decrease relative to group 2. VEGF mRNA was downregulated by 1.5-fold decrease in groups 3-5 when compared to group 2. The expression of XIAP mRNA was downregulated by 1.5, 2, and 1.25-folds in groups 3, 4, and 5 respectively, in comparison with group 2. In comparison to group 2, COX-2 mRNA levels were downregulated by 1.5, 1, and 1-folds in groups 3-5. In groups 3-5, CRP mRNA was downregulated by 2-fold in comparison with group 2. In groups 3-5, p21 mRNA was upregulated by 2, 2.5, and 3-folds, respectively when compared with group 2. It upregulated p53 mRNA by 2.5, 3.5, and 2.5-folds in groups 3-5 in comparison with group 2. It downregulated AFP mRNA by 3.5, 2.5, .2.5-folds in groups 3, 4, and 5 respectively when compared with group 2. Histologic analysis showed that C. sativa extract reduced necrosis and inflammation in HCC.
Conclusion: C. sativa demonstrates anti-hepatocellular carcinoma potentials in an animal model of HCC and with the involvement of Akt. Its anticancer potential is mediated through antiangiogenic, proapoptotic, cycle arrest, and anti-inflammatory mechanisms. In future studies, the mechanisms of anti-HCC effects of Δ-9-tetrahydrocannabinol (Δ-9- THC) and cannabidiol via the PI3K-Akt signaling pathways should be explored.”
“We established that C. sativa demonstrates anti-hepatocellular carcinoma potentials in an animal model of HCC and with the involvement of Akt. THC and cannabidiol form stable hydrophobic and hydrogen bond interactions within the catalytic domain of Akt-2. C. sativa extract reduced the activities of liver function enzymes. It ameliorates lipid peroxidation and increases the antioxidant enzymes’ activities. It shows anti-angiogenic, proapoptotic, and anti-inflammatory effects. It also demonstrates cell cycle arrest. C. sativa extract further demonstrates its anti-HCC effects by moderating necrosis and reduce inflammation in HCC. In future studies, the mechanisms of anti-HCC effects of Δ-9-tetrahydrocannabinol (Δ-9- THC) and cannabidiol via the PI3K-Akt signaling pathways should be explored. Although preclinical trials have demonstrated the clinical efficacy of C. sativa, clinical trials with cancer patients are lacking. It is imperative to review the results of prospective and randomized studies on the use of C. sativa in cancer treatment before drawing any conclusions.”
