Cancer-Cachexia-Induced Human Skeletal Muscle Myotube Degeneration Is Prevented via Cannabinoid Receptor 2 Agonism In Vitro

pubmed logo

“Cachexia syndrome, leading to reduced skeletal muscle and fat mass, is highly prevalent in cancer patients, resulting in further negative implications for these patients. To date, there is no approved therapy for cachexia syndrome. The objective of this study was to establish an in vitro model of cancer cachexia in mature human skeletal muscle myotubes, with the intention of exploiting the cell model to assess potential cachexia therapeutics, specifically cannabinoid related drugs. Having cultured and differentiated primary human muscle myoblasts to mature myotubes, we successfully established two cancer cachexia models using conditioned media (CM) from human colon adenocarcinoma (SW480) and from non-small-cell lung carcinoma (H1299) cultured cells. The cancer-CM-induced extensive myotube degeneration, demonstrated by a significant reduction in mature myotube diameter, which progressed over the period studied. Myotube degeneration is a characteristic feature of cancer cachexia and was used in this study as an index of cachexia. Expression of cannabinoid 1 and 2 receptors (CB1R and CB2R) was confirmed in the mature human skeletal muscle myotubes. Subsequently, the effect of cannabinoid compounds on this myotube degeneration were assessed.

Tetrahydrocannabinol (THC), a partial CB1R/CB2R agonist, and JWH133, a selective CB2R agonist, proved efficacious in protecting mature human myotubes from the deleterious effects of both (SW480 and H1299) cancer cachexia conditions.

ART27.13, a full, peripherally selective CB1R/CB2R agonist, currently being trialled in cancer cachexia (IRAS ID 278450, REC 20/NE/0198), was also significantly protective against myotube degeneration in both (SW480 and H1299) cancer cachexia conditions. Furthermore, the addition of the CB2R antagonist AM630, but not the CB1R antagonist Rimonabant, abolished the protective effect of ART27.13. In short, we have established a convenient and robust in vitro model of cancer-induced human skeletal muscle cachexia. The data obtained using the model demonstrate the therapeutic potential of ART27.13 in cancer-induced cachexia prevention and provides evidence indicating that this effect is via CB2R, and not CB1R.”

“Several cannabinoid drugs have emerged as potential therapeutics for various conditions.”

Characterization of the Chemopreventive Properties of Cannabis sativa L. Inflorescences from Monoecious Cultivars Grown in Central Italy

pubmed logo

“Hemp bioproducts hold great promise as valuable materials for nutraceutical and pharmaceutical applications due to their diverse bioactive compounds and potential health benefits. In line with this interest and in an attempt to valorize the Lazio Region crops, this present study investigated chemically characterized hydroalcoholic and organic extracts, obtained from the inflorescences of locally cultivated Felina 32, USO 31, Ferimon and Fedora 17 hemp varieties. In order to highlight the possible chemopreventive power of the tested samples, a bioactivity screening was performed, which included studying the antimutagenic activity, radical scavenging power, cytotoxicity in human hepatoma HepG2 cells, leakage of lactate dehydrogenase (LDH) and modulation of the oxidative stress parameters and glucose-6-phosphate dehydrogenase (G6PDH) involved in the regulation of the cell transformation and cancer proliferation. Tolerability studies in noncancerous H69 cholangiocytes were performed, too. The organic extracts showed moderate to strong antimutagenic activities and a marked cytotoxicity in the HepG2 cells, associated with an increased oxidative stress and LDH release, and to a G6PDH modulation. The hydroalcoholic extracts mainly exhibited radical scavenging properties with weak or null activities in the other assays. The extracts were usually well-tolerated in H69 cells, except for the highest concentrations which impaired cell viability, likely due to an increased oxidative stress. The obtained results suggest a possibility in the inflorescences from the Felina 32, USO 31, Ferimon and Fedora 17 hemp varieties as source of bioactive compounds endowed with genoprotective and chemopreventive properties that could be harnessed as preventive or adjuvant healing strategies.”

Elucidation of GPR55-Associated Signaling behind THC and LPI Reducing Effects on Ki67-Immunoreactive Nuclei in Patient-Derived Glioblastoma Cells

pubmed logo

“GPR55 is involved in many physiological and pathological processes. In cancer, GPR55 has been described to show accelerating and decelerating effects in tumor progression resulting from distinct intracellular signaling pathways. GPR55 becomes activated by LPI and various plant-derived, endogenous, and synthetic cannabinoids.

Cannabinoids such as THC exerted antitumor effects by inhibiting tumor cell proliferation or inducing apoptosis.

Besides its effects through CB1 and CB2 receptors, THC modulates cellular responses among others via GPR55. Previously, we reported a reduction in Ki67-immunoreactive nuclei of human glioblastoma cells after GPR55 activation in general by THC and in particular by LPI. In the present study, we investigated intracellular mechanisms leading to an altered number of Ki67+ nuclei after stimulation of GPR55 by LPI and THC. Pharmacological analyses revealed a strongly involved PLC-IP3 signaling and cell-type-specific differences in Gα-, Gβγ-, RhoA-ROCK, and calcineurin signaling. Furthermore, immunochemical visualization of the calcineurin-dependent transcription factor NFAT revealed an unchanged subcellular localization after THC or LPI treatment. The data underline the cell-type-specific diversity of GPR55-associated signaling pathways in coupling to intracellular G proteins. Furthermore, this diversity might determine the outcome and the individual responsiveness of tumor cells to GPR55 stimulation by cannabinoids.”

Medical cannabis for refractory cancer-related pain in a specialised clinical service: a cross-sectional study

pubmed logo

“Background and objectives: Cancer-related pain management in advanced stages presents a significant challenge that often requires a multidisciplinary approach. Although advancements in pharmacological and interventional therapies, a considerable number of patients still suffer from refractory pain, leading to unmet clinical needs. This study shares our experience with medical cannabis (MC) as a potential therapy for this specific population of patients with cancer-related refractory pain.

Methods: In a cross-sectional study, 252 consecutive refractory cancer-related pain patients (mean age=61.71, SD=14.02, 47.6% males) filled out detailed self-report questionnaires. Of these, 126 patients (55%) were treated with MC and 105 patients (45%) were not.

Results: Most patients received pain management from their oncologist, not a pain specialist. MC was mainly started for pain relief, sleep difficulties and anorexia. About 70% of patients reported subjective improvement from MC, with almost 40% reporting a significant improvement in coping with their illness. Side effects were generally mild, with fatigue and dizziness being the most common (21.78% and 23.46%, respectively). No patient required dedicated medical care for side effects. Of non-users, 65% had tried MC before and stopped due to lack of effectiveness or side effects (39.7% and 34.6%, respectively).

Conclusion: Refractory cancer pain necessitates innovative approaches. This registry highlights that MC can effectively improve symptoms in non-responsive patients, with favourable safety profiles for this vulnerable population.”

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

pubmed logo

“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.”

Synergistic inhibition of glioblastoma multiforme through an in-silico analysis of luteolin and ferulic acid derived from Angelica sinensis and Cannabis sativa: Advancements in computational therapeutics

pubmed logo

“The primary objective of this study is to uncover novel therapeutic agents for the treatment of Glioblastoma Multiforme (GBM), a highly aggressive form of brain cancer, and Alzheimer’s Disease (AD). Given the complexity and resistance associated with both conditions, the study underscores the imperative need for therapeutic alternatives that can traverse the biological intricacies inherent in both neuro-oncological and neurodegenerative disorders. To achieve this, a meticulous, target-based virtual screening was employed on an ensemble of 50 flavonoids and polyphenol derivatives primarily derived from plant sources. The screening focused predominantly on molecular targets pertinent to GBM but also evaluated the potential overlap with neural pathways involved in AD. The study utilized molecular docking and Molecular Dynamic (MD) simulation techniques to analyze the interaction of these compounds with a key biological target, protein tyrosine phosphatase receptor-type Z (PTPRZ). Out of the 50 compounds examined, 10 met our stringent criteria for binding affinity and specificity. Subsequently, the highest value of binding energy was observed for the synergistic binding of luteolin and ferulic acid with the value of -10.5 kcal/mol. Both compounds exhibited inherent neuroprotective properties and demonstrated significant potential as pathway inhibitors in GBM as well as molecular modulators in AD. Drawing upon advanced in-silico cytotoxicity predictions and sophisticated molecular modeling techniques, this study casts a spotlight on the therapeutic capabilities of polyphenols against GBM. Furthermore, our findings suggest that leveraging these compounds could catalyze a much-needed paradigm shift towards more integrative therapeutic approaches that span the breadth of both neuro-oncology and neurodegenerative diseases. The identification of cross-therapeutic potential in flavonoids and polyphenols could drastically broaden the scope of treatment modalities against both fatal diseases.”

The potential of cannabinoids in the treatment of lung cancer

Publikacje pracowników AWF - kwiecień 2023 - Akademia Wychowania Fizycznego  we Wrocławiu

“Introduction: Lung cancer is the number-one cause of death due to neoplasms worldwide. The 5-year overall survival rate is only 22%. In advanced stages, the therapeutic options are limited to chemotherapy, radiotherapy, molecularly targeted therapy and immunotherapy. Phytocannabinoids, the components of Cannabis sativa, their synthetic derivatives and endogenous cannabinoids have demonstrated anticancer activity in various common cancers – breast, prostate, colorectal and lung cancers, among others. The aim of this review was to assess the potential value of cannabinoids in the treatment of lung cancer.

State of knowledge: The majority of preclinical studies demonstrates that cannabinoids inhibit lung cancer cell viability both in vitro and in vivo. The main mechanism of anticancer  activity is the induction of apoptosis, triggered by activation of CB1, CB2 and TRPV1 receptors or independently via other pathways. Cannabinoids influence the components of the tumour microenvironment – cancer associated fibroblasts, macrophages and lymphokine-activated-killer cells. Cannabinoids alter leukocyte infiltration into anti-cancer proportions, inhibit expression of EGFR and PAI-1 and increase the expression of TIMP-1. As a result they induce cytotoxicity, decrease proliferation, migration and invasive potential of lung cancer cells, suppress angiogenesis and metastasis forming. Patients with advanced lung cancer may also benefit from analgesic, antiemetic and appetite improving properties of cannabinoids.

Summary: Cannabinoids can be a supplementary agent in systemic anticancer therapeutic regimen in the future. The exact mechanisms of action, specific doses in anticancer treatment, routes of administration and interactions with other anticancer drugs has yet to be determined. Thus the clinical studies on cannabinoids in lung cancer should be performed in the future.”

Involvement of cannabinoid receptors and adenosine A2B receptor in enhanced migration of lung cancer A549 cells induced by γ-ray irradiation

pubmed logo

“Residual cancer cells after radiation therapy may acquire malignant phenotypes such as enhanced motility and migration ability, and therefore it is important to identify targets for preventing radiation-induced malignancy in order to increase the effectiveness of radiotherapy. G-Protein-coupled receptors (GPCRs) such as adenosine A2B receptor and cannabinoid receptors (CB1, CB2 and GPR55) may be involved, as they are known to have roles in proliferation, invasion, migration and tumor growth. In this study, we investigated the involvement of A2B and cannabinoid receptors in γ-radiation-induced enhancement of cell migration and actin remodeling, as well as the involvement of cannabinoid receptors in cell migration enhancement via activation of A2B receptor in human lung cancer A549 cells. Antagonists or knockdown of A2B, CB1, CB2 or GPR55 receptor suppressed γ-radiation-induced cell migration and actin remodeling. Furthermore, BAY60-6583 (an A2B receptor-specific agonist) enhanced cell migration and actin remodeling in A549 cells, and this enhancement was suppressed by antagonists or knockdown of CB2 or GPR55, though not CB1 receptor. Our results indicate that A2B receptors and cannabinoid CB1, CB2 and GPR55 receptors all contribute to γ-radiation-induced acquisition of malignant phenotypes, and in particular that interactions of A2B receptor and cannabinoid CB2 and GPR55 receptors play a role in promoting cell migration and actin remodeling. A2B receptor-cannabinoid receptor pathways may be promising targets for blocking the appearance of malignant phenotypes during radiotherapy of lung cancer.”

The ameliorative effects of cannabidiol on methotrexate-induced neuroinflammation and neuronal apoptosis via inhibiting endoplasmic reticulum and mitochondrial stress

pubmed logo

“Methotrexate (MTX) is an antineoplastic agent and has neurotoxic effects. It exerts its toxic effect on the brain by triggering inflammation and apoptosis. Cannabidiol (CBD) is an agent known for its antioxidant, anti-inflammatory effects in various tissues. The aim of this study is to examine the protective effects of CBD treatment in various brain structures from MTX damage and to evaluate the effect of intracellular pathways involved in apoptosis. Thirty-two adult Wistar Albino female rats were divided into four groups as control, MTX (20 mg/kg intraperitoneally [i.p.]), MTX + CBD (0.1 mL of 5 mg/kg i.p.), and CBD (for 7 days, i.p.). At the end of the experiment, brain tissues collected for biochemical analyses as total oxidant status (TOS), total antioxidant status, oxidative stress index (OSI), histopathological and immunohistochemical analyses as tumor necrosis factor-α (TNF-α), serotonin, mammalian target of rapamycin (mTOR) staining, genetic analyses as caspase-9 (Cas-9), caspase-12 (Cas-12), C/EBP homologous protein (CHOP), and cytochrome-c (Cyt-c) gene expressions. In the histopathological and immunohistochemical evaluation, hyperemia, microhemorrhage, neuronal loss, and significant decreasing expressions of seratonin were observed in the cortex, hippocampus, and cerebellum regions in the MTX group. mTOR, TNF-α, Cas-9, Cas-12, CHOP, and Cyt-c expressions with TOS and OSI levels were increased in the cortex. It was observed that these findings were reversed after CBD application in all regions. MTX triggers neuronal apoptosis via endoplasmic reticulum and mitochondrial stress while destroying serotonergic neurons. The reversal of the pathological changes with CBD treatment proves that it has anti-inflammatory and antiapoptotic activity in brain.”

Rationalizing a prospective coupling effect of cannabinoids with the current pharmacotherapy for melanoma treatment

pubmed logo

“Melanoma is one of the leading fatal forms of cancer, yet from a treatment perspective, we have minimal control over its reoccurrence and resistance to current pharmacotherapies. The endocannabinoid system (ECS) has recently been accepted as a multifaceted homeostatic regulator, influencing various physiological processes across different biological compartments, including the skin. This review presents an overview of the pathophysiology of melanoma, current pharmacotherapy used for treatment, and the challenges associated with the different pharmacological approaches. Furthermore, it highlights the utility of cannabinoids as an additive remedy for melanoma by restoring the balance between downregulated immunomodulatory pathways and elevated inflammatory cytokines during chronic skin conditions as one of the suggested critical approaches in treating this immunogenic tumor.”

“Cannabinoids, including endocannabinoids, phytocannabinoids, and synthetic agents, exert pharmacological effects on the skin by activating the specific cannabinoid receptors CB1 and CB2. Uniquely, the ECS system has been shown in vivo and in vitro to regulate the immune system through its immunomodulatory properties. They can attenuate chronic inflammatory disorders and subsequently enhance anti-tumor characteristics. In addition to their immunomodulatory effects, cannabinoids further mediate multiple anti-cancer pathways, including autophagy, apoptosis, angiogenesis, cell motility, and cell adhesion; moreover, they regulate key inflammatory processes critical to the homeostatic regulation of the tumor microenvironment. “