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Voicu, V.; Brehar, F.; Toader, C.; Covache-Busuioc, R.; Corlatescu, A.D.; Bordeianu, A.; Costin, H.P.; Bratu, B.; Glavan, L.; Ciurea, A.V. The Relationship between Cannabinoids and Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/49513 (accessed on 03 August 2024).
Voicu V, Brehar F, Toader C, Covache-Busuioc R, Corlatescu AD, Bordeianu A, et al. The Relationship between Cannabinoids and Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/49513. Accessed August 03, 2024.
Voicu, Victor, Felix-Mircea Brehar, Corneliu Toader, Razvan-Adrian Covache-Busuioc, Antonio Daniel Corlatescu, Andrei Bordeianu, Horia Petre Costin, Bogdan-Gabriel Bratu, Luca-Andrei Glavan, Alexandru Vlad Ciurea. "The Relationship between Cannabinoids and Cancer" Encyclopedia, https://encyclopedia.pub/entry/49513 (accessed August 03, 2024).
Voicu, V., Brehar, F., Toader, C., Covache-Busuioc, R., Corlatescu, A.D., Bordeianu, A., Costin, H.P., Bratu, B., Glavan, L., & Ciurea, A.V. (2023, September 22). The Relationship between Cannabinoids and Cancer. In Encyclopedia. https://encyclopedia.pub/entry/49513
Voicu, Victor, et al. "The Relationship between Cannabinoids and Cancer." Encyclopedia. Web. 22 September, 2023.
The Relationship between Cannabinoids and Cancer
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This entry is adapted from the peer-reviewed paper 10.3390/biom13091388

Cannabis is an impressively complex plant, boasting more than 100 cannabinoids in addition to various terpenes and flavonoids. Medical cannabis has seen a rapid expansion in recent years as more patients turn to using it as a solution for various ailments. With more patients turning to this botanical remedy for treatment purposes, a growing demand exists among the scientific and medical communities to investigate how cannabis orchestrates its effects within the body; this goes beyond simply understanding potential merits and risks. The National Cancer Institute acknowledges the therapeutic potential of Cannabis sativa, particularly Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), in alleviating various symptoms associated with cancer, including pain, appetite loss, nausea, and anxiety. 

cannabinoids cancer

1. Introduction

1.1. Cannabinoids

The burgeoning field of research surrounding Cannabis sativa has identified Δ9-tetrahydrocannabinol (THC) as one of its key active compounds. This compound, along with a plethora of related molecules, both phytochemical and synthetic, exhibits an affinity for specific neuronal binding sites, contributing to an altered mood and perceptions. These binding locations are particularly abundant in neural structures such as the substantia nigra, hippocampus, and cerebellum. One of the clinical manifestations associated with excessive cannabis consumption is cannabinoid hyperemesis syndrome (CHS), a condition characterized by recurrent episodes of severe vomiting. This syndrome is exacerbated by the consumption of high doses of cannabinoids and has imposed a growing burden on healthcare systems, particularly in the United States. Despite the increasing prevalence of CHS, the medical community has yet to reach a consensus on optimal treatment strategies [1][2].
Beyond their well-documented medicinal applications, cannabinoids have been the subject of intensive investigations aimed at exploring their therapeutic potential for a variety of medical conditions, including pain, addiction, obesity, and inflammation, among others. Recent discoveries have expanded our understanding of the pharmacology of cannabinoids by revealing the existence of non-CB1 and non-CB2 orphan G-protein-coupled receptors such as GPR18, GPR55, and GPR119. These receptors operate in conjunction with the established CB1 and CB2 receptors but have unique characteristics, including allosteric binding and biased signaling, which could lead to distinct functional outcomes. A particularly intriguing line of inquiry has revealed the presence of CB1 receptors within the mitochondria of striated and cardiac muscles, implicating them in the modulation of intramitochondrial signaling and respiratory processes [3][4][5].

1.2. Importance of Endogenous Cannabinoids

The endocannabinoid system (ECS) represents a complex neuromodulatory network that is of paramount significance to the central nervous system (CNS), synaptic plasticity, and adaptive responses to both endogenous and environmental stimuli. Comprising cannabinoid receptors (CBRs), endogenously synthesized cannabinoids (endocannabinoids), and enzymatic pathways for their synthesis and degradation, the ECS serves as a critical mechanism for neuromodulation. While CB1 cannabinoid receptors are the most commonly implicated receptors in these interactions, other receptors such as CB2, transient receptor potential channels, and peroxisome proliferator-activated receptors also participate [5][6].
Two endogenous cannabinoids that have attracted significant academic attention are 2-arachidonoyl glycerol (2-AG) and arachidonoyl ethanolamide (anandamide). Despite sharing molecular similarities, these cannabinoids diverge in their synthetic and degradative enzymatic pathways, leading to distinct physiological and pathophysiological roles [7][8].
The societal ubiquity of cannabis consumption has fueled a wealth of research into the physiological and pathophysiological functions of endocannabinoids. Marijuana’s prevalence as a widely consumed substance in Western societies contributed to the discovery of the ECS and elucidated its involvement in a plethora of physiological processes. This intricate system comprises G-protein-coupled CBRs that are activated by lipid mediators, commonly referred to as endocannabinoids (eCBs). These eCBs are not only synthesized from cannabis but also encompass a variety of biochemical constituents including precursors, enzymes, and transporters. Research has revealed an extensive distribution of components of the ECS throughout various bodily regions and organs, underscoring its fundamental role in physiology and the potential for targeted interventions for a range of human ailments [9][10][11][12].
Historically, Cannabis sativa (marijuana) has been employed to stimulate appetite, but rigorous scientific scrutiny of its molecular mechanisms gained momentum following the identification of THC in the late 1960s. Although marred by societal disapproval due to misuse, empirical evidence has highlighted the therapeutic potential of marijuana and its derivatives. Specifically, they have been found to enhance appetite for sweet foods. The elucidation of distinct CBRs and their endogenous ligands has provided a robust physiological framework for understanding the myriad biological effects mediated by marijuana and other cannabinoids [13][14].
Recent advancements in the field have illuminated the existence of a plethora of naturally occurring compounds that serve as binding partners to CBRs. eCBs bear a functional resemblance to endorphins and have been detected in a range of mammalian species, including humans. Notably, eCBs have been identified in a diverse array of tissues such as the CNS, peripheral nerves, and reproductive and immune organs like the uterus, leukocytes, spleen, and testicles. Anandamide, one of the earliest-discovered eCBs, is present in notably high concentrations in uterine tissue [15]. This suggests a pivotal role in reproductive processes, a notion corroborated via extensive investigations. Empirical studies have revealed anandamide’s crucial involvement in orchestrating implantation processes. A diminished enzymatic activity responsible for the breakdown of anandamide has been frequently associated with early pregnancy loss [16][17]. The growing body of scientific literature on eCBs has notably concentrated on the study of anandamide, reaffirming its significance in both physiological and pathophysiological contexts.

1.3. Cancer

THC demonstrates interactions with CBRs, chiefly CB1 and CB2, which are naturally activated by eCBs. The compound plays a multifaceted role in various physiological and pathological domains, including the modulation of the release of neurotransmitters, the regulation of pain perception, and the functioning of the cardiovascular, digestive, and hepatic systems. Nonetheless, THC’s psychotropic effects, which are mainly mediated via the activation of CB1 receptors in the brain, have considerably restricted its clinical applicability. Contrastingly, the cannabis plant is replete with cannabinoids that exhibit minimal to no psychotropic activity, many of which have demonstrated therapeutic potential surpassing that of THC. Among these, cannabidiol (CBD) has gained prominence for its prospective utility in treating conditions such as inflammation, diabetes, cancer, affective disorders, and neurodegenerative diseases. Another cannabinoid, D9-tetrahydrocannabivarin (THCV), shows promise in addressing issues like epilepsy and obesity [18][19].
CBD’s antioxidative properties have revealed its potential in combating neurodegenerative and cardiovascular disorders. Moreover, animal studies have showcased CBD’s anticancer properties. The co-administration of THC with radiation therapy has also been observed to induce higher rates of autophagy and apoptosis in cancer cells. The National Cancer Institute acknowledges the therapeutic potential of Cannabis sativa, particularly THC and CBD, in alleviating various symptoms associated with cancer, including pain, appetite loss, nausea, and anxiety. CBD’s complex pharmacological profile allows it to act as an adaptogen and modulator, interacting intricately with the receptor proteins CB1 and CB2, among other sites [20].
Case reports in the medical literature affirm the therapeutic viability of cannabinoids derived from Cannabis sativa. However, the clinical adoption of these compounds is often hindered by the psychotropic side effects that are predominantly attributable to THC. Advancements in the understanding of the ECS, including the discovery of new receptors, ligands, and mediators, have facilitated the exploration of novel therapeutic avenues that could mitigate the adverse psychotropic effects associated with certain plant constituents. Such scientific innovations have catalyzed the development of FDA-approved medications that are revolutionizing contemporary medical treatment modalities. For instance, Nabiximols, an FDA-sanctioned amalgam of THC and non-psychoactive CBD, has demonstrated utility in alleviating the pain and spasticity related to multiple sclerosis [21][22]. Additionally, DRO and Nabilone have gained FDA approval for their effectiveness in countering chemotherapy-induced nausea and vomiting in cancer patients. Notably, DRO has also secured regulatory endorsement for its role in managing anorexia among AIDS patients [23][24][25][26].

2. Cannabinoids and Cancer

2.1. Antitumor Effects of Cannabinoids

The investigation into cannabinoids as potential anticancer agents has expanded in recent years, although it remains relatively nascent. Limited to a small number of human studies, including one phase I/II clinical trial and three experimental studies, the body of evidence does reveal some promise. One of these studies distinguished itself through a rigorous methodological approach, aligning closely with the evaluation criteria outlined by the Cochrane Collaboration Manual. This meticulousness facilitated a more reliable interpretation of its experimental methodologies and outcomes, accentuating the need for further high-quality research to substantiate the antitumor effects of cannabinoids. Beyond merely serving as palliative agents in cancer treatment, cannabinoids hold potential as primary or adjunctive antineoplastic agents. However, the need for an expansive array of well-designed clinical trials remains critical for validating the antitumor efficacy of cannabinoids in oncological settings [27].
Recent advancements have particularly spotlighted the antiproliferative attributes of CBD, a nonpsychoactive cannabinoid. In a focused in vitro study examining the effects of CBD on U87 and U373 human glioma cell lines, a significant reduction in the mitochondrial oxidative metabolism was observed, along with a decrease in cell viability. The antiproliferative impact was noted within 24 h of exposure to CBD and was partially attenuated by specific agents like SR144528 and α-tocopherol. Intriguingly, other cannabinoid antagonists failed to reverse CBD’s effects. For the first time, the study linked CBD’s antiproliferative activity with the induction of apoptosis, which was confirmed via a cytofluorimetric analysis and single-strand DNA staining. Furthermore, in vivo studies on nude mice implanted with U87 human glioma cells demonstrated significant tumor reductions following the subcutaneous administration of CBD, reinforcing its potential role as an antineoplastic agent. These findings contribute substantially to our understanding of CBD’s antitumor properties, both in vitro and in vivo, advocating for its further exploration as a potential antineoplastic agent [28].
The therapeutic potential of Cannabis sativa, particularly its bioactive components like cannabinoids and terpenes, has garnered substantial attention in contemporary research. In a study involving female C57BL/6 mice treated with azoxymethane (AOM) and dextran sulfate sodium (DSS), THC exhibited both anti-inflammatory and antitumoral properties [29]. THC administration led to marked reductions in the severity of inflammation and tumor formation, as evidenced via the hematoxylin and eosin staining of the colonic tissue. Additionally, THC was found to mitigate the production of interleukin-22, a cytokine implicated in inflammation-driven colon cancer, by intraepithelial cells. Both cannabinoids and terpenes such as β-caryophyllene, limonene, and myrcene have demonstrated promise in inducing apoptosis, inhibiting cell proliferation, and suppressing angiogenesis in colorectal cancer (CRC). Of significance is the synergistic interaction between cannabinoids and terpenes, which may amplify therapeutic efficacy in treating CRC [30].
In a separate investigation focused on elucidating the antitumoral mechanisms of cannabinoid compounds, particularly those that are high in CBD, three extracts of Cannabis sativa were evaluated. The study centered on their effects on cell mortality, cytochrome C oxidase activity, and lipid composition in SH-SY5Y neuroblastoma cells. The results indicated that these extracts induce cell mortality by inhibiting the activity of cytochrome C oxidase. Importantly, this cytotoxicity was comparable to the cytotoxicity induced by known cannabinoid agonists like WIN55,212-2. While this effect could be partially attenuated by the selective CB1 receptor antagonist AM281 and antioxidants like α-tocopherol, it underscores the critical role of oxidative stress in mediating the antitumoral properties of cannabinoids. Furthermore, the extracts with high CBD contents revealed diverse antitumoral effects against human neuroblastoma cells which appeared to operate via multiple mechanisms, not only by affecting cannabinoid receptor activity but also by disrupting mitochondrial electron transport and increasing oxidative stress. Interestingly, the study suggested that whole-plant extracts may offer superior antitumoral effects compared to isolated cannabinoids. However, the study did not account for the potential mitigating impact of antioxidants, such as α-tocopherol. This omission is noteworthy since α-tocopherol, a well-known antioxidant commonly used to alleviate adverse reactions in chemotherapy, could potentially diminish the antitumoral efficacy of cannabinoid-based treatments [31].

2.2. Cannabinoids in Cancer Therapy

The expression levels of cannabinoid receptors (CB-Rs), particularly CB1-R and CB2-R, in breast cancer tissues have been illuminated through microarray technology analysis. The findings indicate that while CB1-R immunoreactivity was observed in 28% of carcinoma samples, a staggering 72% displayed CB2-R immunoreactivity. This is in stark contrast to non-transformed mammary tissues, which showed negligible immunoreactivity for both CB1-R and CB2-R. The association between elevated CB2-R expression and increased tumor aggressiveness is noteworthy. For instance, tumors devoid of estrogen and/or progesterone receptors, which generally have a poorer prognosis, frequently exhibit elevated levels of CB2-R. This trend is also seen in particularly challenging triple-negative tumors, which are characterized by their lack of both steroid hormone receptors and HER2/neu receptors. These tumors often display high CB2-R levels which correlate with poor differentiation, an increased likelihood of early local recurrence, and distant metastasis. The therapeutic landscape for breast cancer could potentially be revolutionized by targeting CB-Rs, particularly CB2-R and CB1-R. This avenue may offer effective treatment options for patients who experience recurrence post anti-HER2-targeted therapies. Beyond CB1-R and CB2-R, other CB-Rs like GPR55 also merit attention. The elevated expression of GPR55 has been observed in metastatic MDA-MB-231 cells, and its proliferative effects are thought to be linked to extracellular signal-regulated kinase (ERK) activation and the subsequent expression of the c-FOS proto-oncogene. Furthermore, cannabinoids (CBs) present potential therapeutic agents for challenging HER2-expressing breast tumors. Combining CBs with targeted therapies like lapatinib, a tyrosine kinase inhibitor, may potentiate antitumoral effects and enhance synergy with conventional chemotherapy agents such as cisplatin. Empirical studies have corroborated the synergistic effect between CBs and other oncologic agents including cisplatin [32][33][34].
From a translational standpoint, the synergistic potential of cannabinoids with existing chemotherapy treatments should not be overlooked. Preclinical studies have demonstrated that CBD and THC in particular can enhance the effectiveness of conventional chemotherapies. Although the scientific literature has yet to present data on the possible synergies between FAAH or MAGL inhibitors and classical chemotherapy or immunotherapies, cannabinoids have already been successfully employed in a clinical setting to mitigate the side effects associated with chemotherapy, such as nausea, vomiting, and pain. Recent work has also indicated the utility of MAGL inhibitors like MJN110 in reversing chemotherapy-induced neuropathy. Consequently, future research endeavors should prioritize combination studies with traditional chemotherapy agents to evaluate potential synergistic effects on tumor growth inhibition and metastasis reduction while simultaneously assessing the ability to alleviate chemotherapy-induced side effects [35][36].
In parallel, CBD has garnered an increasing amount of research interest for its analgesic properties in neurologically mediated conditions. One notable pharmacological formulation, Nabiximols (Sativex), which is a composite of CBD and THC, has gained regulatory approval in specific jurisdictions for mitigating spasticity associated with multiple sclerosis and as an adjunct in cancer-related pain management. CBD’s interaction profile is broad, encompassing not just the canonical CB1R and CB2R but also other receptors like TRPVs, 5-HT1A, GPR55, and PPARg. In the realm of oncology, CBD has exhibited anticancer properties through various mechanisms, including the induction of apoptosis and the inhibition of cell migration and metastasis across diverse cancer types [37].
Adding to the complexity of the cannabinoid landscape are compounds like cannabigerol (CBG), O-1602, and URB-602, which have shown promising anti-neoplastic effects in experimental models, notably in decreasing tumor volume and averting the formation of aberrant crypt foci (ACF) [38].
The ECS has emerged as a focal point of medical research owing to its regulatory role in an array of physiological and pathological processes, encompassing pain modulation and memory formation. Deviations in the activity of the ECS have been identified across a gamut of medical conditions, ranging from oncological to neurodegenerative disorders such as Parkinson’s disease, Huntington’s chorea, and multiple sclerosis (MS). Consequently, pharmacological interventions aiming to modulate the activity of the ECS have gained considerable momentum, often employing plant-derived or synthetic cannabinoids as active agents. Such pharmacological strategies have yielded tangible benefits in clinical contexts such as AIDS-related cachexia and MS-associated spasticity, among other palliative care applications. Prominent examples of these pharmaceutical agents include Sativex, a standard plant extract formulation of nabiximols, and synthetic compounds like Nabilone (Cesamet) and DRO (Marinol). While preliminary evidence suggests a potential utility of oral cannabinoids in ameliorating chemotherapy-induced nausea and vomiting (CINV), further empirical investigations are requisite to substantiate and consolidate this therapeutic application [39].

2.3. Potential Mechanisms of Cannabinoid-Mediated Anticancer Effects

Cannabinoids’ neuroprotective and antioxidant effects are produced via several complex mechanisms, the primary one of which is their effect on mitochondrial function. CB receptors typically reside on cell membranes. However, 30% of neuronal mitochondria contain CB1 receptors on their outer membranes, evidence that cannabinoids play an integral role in energy balance through the modulation of the mitochondrial electron transport chain (mETC), thus impacting learning processes as well as other physiological processes. The activation of the mitochondrial CB1 receptor pathway involves multiple components, including the Gai protein, soluble-adenylyl cyclase (sAC), and protein kinase A (PKA) [40][41]. Studies have also demonstrated that cannabinoids influence OXPHOS via non-receptor mechanisms, as supported by previous research [42]. Another study provides further evidence of a correlation between the inhibition of cytochrome C oxidase activity in SH-SY5Y cell lines and the concentration of THC in Cannabis sativa extracts and their ability to modulate the metabolism as well as the cannabinoids’ involvement in mitochondria-related toxicity and oxidative stress [31]. Cannabinoids’ production of ROS has been shown to cause changes to cell membranes, including the peroxidation of lipids that affect normal and cancer cells alike [43].
Limonene, a cyclic monoterpene found in citrus fruit peel oils, has been demonstrated to exert notable anticancer properties both in vitro and in vivo across various types of cancer. It can reduce tumor growth while simultaneously inducing apoptosis through multiple pathways. Limonene displayed significant cytotoxicity against T24 human bladder cancer cells by inducing G2/M-phase cell cycle arrest, decreasing migration and invasion, increasing apoptosis rates, and upregulating Bax/caspase-3 expression levels while attenuating Bcl-2 [44]. Limonene produced changes in gene regulation related to apoptosis, signal transduction, inflammation, and DNA repair within HepG2 cells. D-limonene demonstrated similar results in colon cancer cells, where it inhibited cell viability by inducing apoptosis through intrinsic pathway activation and suppressing PI3K/Akt activity [45]. For gastric cancer cells, however, the activation of the mitochondria-mediated intrinsic pathway was evidenced. Notably, the combination of limonene and berberine yielded amazing anticancer effects that surpassed their individual potencies [46]. Neuroblastoma cells were observed to exhibit autophagy through lipidated Light chain 3 (LC3) independent of the generation of ROS or ERK activation and in conjunction with decreased levels of p62 protein [47]. Lung cancer cell lines also displayed autophagy; D-limonene showed promising results at curtailing tumor growth in murine models [48]. D-limonene caused cell apoptosis through two distinct mechanisms in murine T-cell lymphoma cells: at lower concentrations, it caused the production of H2O2 and activated the ERK pathway, while at higher concentrations, it inhibited protein farnesylation and the production of O2 [49]. Niosomes containing 20uM D-limonene showed significant cytotoxicity against HepG2 cell lines as well as other cell lines; when combined with docetaxel, the effect was further amplified through an escalation in the production of ROS and an increase in the expression of apoptotic proteins, suggesting the involvement of the mitochondrial apoptosis pathway [50].
In an exploration of the mechanistic underpinnings of CBD and CBG treatments, one study focused on their impact on the expression of genes that are pertinent to cannabinoid activity and the pathobiology of mesothelioma. Notably absent from this analysis was CNR2 as its expression was not observed across any mesothelioma cell lines. The treatments with both CBD and CBG led to the substantial upregulation of key genes associated with cannabinoid activity and the pathology of mesothelioma across the three mesothelioma cell lines examined [51]. Specifically, noteworthy upregulations were observed for cannabinoid CB1 receptor (CNR1), G-protein-coupled receptor 55 (GPR55), and 5-HT1a receptor (5HTR1A) when compared to vehicle-treated controls, with an approximately 50-fold increase in the expression of GPR55. Interestingly, the CBD treatment had a variable impact on the mRNA expression of transient receptor potential vanilloid type 1 (TRPV1). While it influenced the expression of TRPV1 across most mesothelioma cell lines, an exception was noted in the case of H2452 cells [51]. The expression of TRPV2 or peroxisome proliferator-activated receptor gamma (PPARG) demonstrated cell-line-dependent variability. Moreover, CBD treatment led to a reduction in the endogenous CXCR4 agonist C-X-C motif chemokine 12 (CXCL12), while CBG’s effects on CXCL12 expression varied across different cell lines. To delve deeper into the mechanistic landscape, gene pathway analyses were conducted. Both CBD and CBG were observed to similarly influence cell cycle regulation pathways. Intriguingly, the Gaq/PLC signaling pathways may have been disrupted through the upregulation of GPR55 receptors by cannabinoids, affecting calcium homeostasis [52]. Furthermore, CBG appeared to stimulate the nuclear factor of activated T cells (NFAT) signaling pathways, a group of transcription factors that could also be activated via GPR55 receptors. Among the salient findings was the consistent activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) by both CBD and CBG. NF-kB is implicated in multiple inflammatory pathways, including the release of various cytokines and chemokines (such as CXCL12-CXCR4), along with cell cycle regulators, anti-apoptotic factors, and adhesion molecules. Overall, these preliminary results underscore the impact of CBD and CBG on human mesothelioma cell lines, indicating a clear avenue for further investigation [53].
In a subsequent investigation, a research team explored the antitumoral potential of WIN 55,212-2 against pediatric osteosarcoma. The study delineated that WIN 55,212-2 induced cell cycle arrest and prompted the upregulation of crucial markers of endoplasmic reticulum stress such as GRP78, CHOP, and TRB3, followed by autophagy [54][55][56]. These findings align with previously reported mechanisms in adult cancers. For example, Fisher et al. conducted a study on the impact of both THC and CBD on pediatric neuroblastoma cells, revealing significant reductions in cell viability. Additionally, CBD was observed to inhibit xenograft growth in vivo. Although the precise mechanisms underlying CBD’s antitumoral effects remain to be elucidated, the compound induced apoptosis in neuroblastoma cells both in vitro and in vivo, effectively causing cell death directly and indirectly [57].
Collectively, these preclinical findings demonstrate the prospective anticancer efficacy of cannabinoids against a range of pediatric cancers, albeit via multiple mechanisms. It is important to recognize that pediatric cancers are heterogeneous, originating from various cell types and tissues and often driven by specific mutations. One limitation of these studies is their reliance on long-term cultured cell lines that may not fully represent the complexity of human cancers. Furthermore, a dearth of studies have corroborated their findings through animal models or orthotopically xenografted models, consequently failing to replicate the authentic tissue contexts of these malignancies [58]. Moreover, no clinical trials have assessed the potential antitumoral effects of cannabinoids in the treatment of pediatric cancer. Anecdotal evidence exists, however, suggesting potential benefits. For instance, Foroughi et al. reported two cases of female patients experiencing spontaneous regressions of low-grade glioma coinciding with cannabis inhalation. While a retrospective study linked the expression of CB1R to tumor regression, suggesting a plausible mechanism, Foroughi et al. did not investigate CB1R expression in their reported cases [59][60].
A growing body of literature supports the notion that the therapeutic benefits of cannabis are not merely attributable to individual constituents but are the result of synergistic interactions among various compounds within the plant. For instance, evidence has emerged that a holistic botanical preparation of cannabis exhibits greater potency in both in vitro and in vivo models for breast cancer treatment compared to isolated 9-THC [61]. Furthermore, in vivo experiments yielded compelling results, showing additive effects when cannabis terpenes such as α-humulene and β-pinene were combined with WIN55,212-2 in mouse models [62]. These findings suggest that the inclusion of terpenes enhances the activity of isolated cannabinoids, likely through a synergistic mechanism. Parallel lines of inquiry have delved into the molecular mechanisms underlying potential pharmacological interventions against prostate cancer. Various prostate cancer cell lines, including PC3, DU145, and LNCaP, have demonstrated reduced migration, implicating cannabinoids as promising agents in combating cancer cell motility. Specifically, the CB1 agonist WIN-55,212 was observed to decrease the activity of RhoA GTPase, a critical regulator of cell migration [63]. This led to a subsequent disruption in actin/myosin microfilament formation and a reduction in cell migration. Reinforcing RhoA protein activity resulted in an increase in microfilament formation and cell spreading, whereas the exogenous CB1 agonist anandamide mimicked the reduction by disrupting actin/myosin microfilaments. In this context, Roberto et al. reported significant, dose-dependent decreases in the migration and invasion capabilities of PC3 and DU145 cells when treated with the synthetic cannabinoid WIN-55,212 [64].

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Victor Voicu
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Razvan-Adrian Covache-Busuioc
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Antonio Daniel Corlatescu
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Horia Petre Costin
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Bogdan-Gabriel Bratu
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