Phytocannabinoids and Their Potential Use As a Phytochemotherapy

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Narrative Review: Phytocannabinoids and their Potential Use as a Phytochemotherapy

Suttithumsatid W1 and Panichayupakaranant P1,2* Review Article 1Department of Pharmacognosy and Pharmaceutical Botany, Prince of Songkla University, Volume 4 Issue 3 Thailand Received Date: November 15, 2020 2Phytomedicine and Pharmaceutical Biotechnology Excellence Center, Faculty of Published Date: November 30, 2020 Pharmaceutical Sciences, Prince of Songkla University, Thailand DOI: 10.23880/ipcm-16000209

*Corresponding author: Pharkphoom Panichayupakaranant, Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat-Yai 90112, Thailand, Tel: +66- 74-288980; Email: [email protected]

Abstract

Cannabis sativa L. has been used as an herbal medicine for centuries. This plant is a natural source of cannabinoids, including

research topic on their therapeutic properties. The human endocannabinoid system generally consists of receptors, endogenous ligands,Δ-9-tetrahydrocannabinol and metabolizing (THC)enzymes, and and cannabidiol plays an (CBD), important the two role major in various phytocannabinoids physiological thatand havepathological been a recently effects. interested Based on cancer therapy, phytocannabinoids have mainly been used for palliative care treatment, i.e. relieving nausea and vomiting caused by chemotherapy and stimulating appetite. Additionally, in many preclinical experiments, including in vitro and in vivo studies, cannabinoids have exhibited anticancer effects against numerous cancer cell lines through various mechanisms. For example, THC induced apoptosis of cancer cells via cannabinoid receptors by a stimulation of ceramide synthesis led

to an activation of the endoplasmic reticulum stress-related signaling pathway, and the induction of autophagy through a calmodulin-activated kinase kinase β. In contrast, the anticancer activity of CBD is related to other types of receptors, i.e. orphan G-protein coupled receptor 55 (GPR55), transient receptor potential vanilloid receptor 1 (TRPV1), transient receptor to induced cancer cell death. Although, there are many reports on anticancer properties of phytocannabinoids, in vitro and potential melastatin 8 (TRPM8), which mainly relied on the stimulation of reactive oxygen species (ROS) production, leading in vivo phytochemotherapy. , high quality clinical trials concerning their efficacy and safety are still essential to approve their potential use as a Keywords: Cannabis sativa; Cannabinoid; Cancer; Tetrahydrocannabinol; Cannabidiol ; HPLC

Introduction

todeaths) 23.6 million and breast by 2030 cancer [1]. Currently, (627,000 conventional deaths), respectively. medicine of abnormal cells that affect the human body. Cancer is a playsThe number an important of new role cancer in cancer cases pertreatment. year is expectedThere are to many rise seriousCancer global is public a generic health term problem for the and uncontrolled the second leading growth routes of cancer treatment depending on types of cancer, cause of death that estimated 9.6 million deaths in 2018. the levels of invasion and the performance status of patients

The most common causes of cancer death were lung cancer or[2]. radiation However, therapy. most patients In addition, commonly immunotherapy, need a combination targeted (1.76 million deaths); colorectal cancer (862,000 deaths); of treatments, such as surgery with chemotherapy and/ liver cancer (828,945 deaths); stomach cancer (783,000 Narrative Review: Phytocannabinoids and their Potential Use as a Phytochemotherapy Int J Pharmacogn Chinese Med 2 International Journal of Pharmacognosy & Chinese Medicine

cancer therapy, cannabinoids have recently been used for palliative care, i.e. relieving nausea and vomiting caused by especiallytherapy, and from hormone systemic therapy chemotherapy, also have benefitsare often in severe,cancer suchtreatment as [2,3].cardiotoxicity, Moreover, bladderside effects toxicity, of cancer neurotoxicity, treatment, preclinical experiments including in vitro and in vivo studies renal toxicity, gastrointestinal toxicity, hepatotoxicity, and havechemotherapy revealed and that stimulating cannabinoids appetite possessed [17]. However, anti-tumor many effects against numerous cancer cell lines through various mechanisms [18,19]. Nevertheless, anticancer effects of hematopoietic system injury. Subsequently, these adverse cannabinoids appear to be dependent on the type of cancer effectsCurrently, may be apotential major cause strategies of therapy to manage discontinuation adverse effect[4,5]. from cancer treatment focus on alternative treatments, especially the use of natural products including crude herbal and concentration of cannabinoids [20]. This review aims to botanicalsummarize sources, the scientific physicochemical studies on anticancerproperties, potentials biogenesis, of anticancer agents are being clinically used to treat or prevent quantitativeTHC and CBD. HPLC Moreover, analysis, important and toxicity information, assessment including are developmentextracts and pureof cancer. phytochemicals These plants-derived [4]. Many plant-derived anticancer described. agents can be divided into 4 groups, namely Vinca alkaloids Catharanthus roseus Taxus Taxus Retrieval Strategies and Methods brevifolia Podophyllum Podophyllum peltatum (fromand P. hexandrum ), Camptotheca diterpenes (from Cannabis Camptotheca), acuminate lignansVinca (from alkaloids, i.e. vinblastine sativa, cannabinoid, endocannabinoid, phytocannabinoid, and vincristine, are), common and allopathic medicine alkaloids used (from for anticancer,Based on thisantitumor, narrative review,tetrahydrocannabinol, the keywords of and treatment of Hodgkin’s) [6].disease and acute lymphoblastic leukemia in children by inhibiting the dynamics of (https://pubmed.ncbi.nlm.nih.gov/ advancedcannabidiol) were searched in the online search engines, ® Taxus including PubMed themicrotubules microtubule by disruptorsbinding to forβ-tubulin treatment in the of ovarian,mitotic spindlebreast, , Science Direct. (https://www.sciencedirect.com/ lung,[7,8]. Paclitaxelhead, and (Taxol neck cancers) is a [9,10]. diterpene Podophyllotoxin widely used is asa search) and Google (https://www.google.com) to obtain 100 podophyllum lignan that has been used for treatment of selected scientific articles Most of them have been published numerous cancers including testicular, breast, pancreatic, betweenCannabinoids 2006-2020. lung, stomach, and ovarian cancers. A mechanism of action Endocannabinoids: Basically, cannabinoids can be preventing cell division [11]. Camptothecin, a Camptotheca divided into 3 groups, namely endocannabinoids, alkaloidof podophyllotoxin that has been is basedused as on a broad-spectrum binding with tubulin, anticancer thus phytocannabinoids and synthetic cannabinoids [20]. agent for different types of cancer patient, such as small- Endocannabinoids are the endogenous ligands that are cell and non-small cell lung, breast and liver cancers [12]. produced in the human body and bind to the cannabinoid Camptothecin binds to the topoisomerase I and DNA complex, thus causing DNA damage and resulting in cell N apoptosis [13,14]. receptors. Two major endocannabinoids, anandamide ( -arachidonoylethanolamine; AEA) and 2-arachidonoyl Cannabis sativa has been used as an herbal medicine inglycerol response (2-AG) to haveincrease been intracellular identified asCa arachidonic2+ concentration acid for centuries. It is a natural source of natural cannabinoids, and/orderivatives to (Figureactivate 1), Gq/11-coupled which are produced receptor on demand[21,22]. Endocannabinoids are produced from postsynaptic pharmacologicalincluding Δ-9-tetrahydrocannabinol properties [15]. Therefore, medical (THC) use of and C. retrograde signaling systems in the brain [23]. AEA acts as sativacannabidiol (CBD), which have been investigated for their terminals following neuronal activation and mediated investigation and publication. The endocannabinoid systemhas consisting recently beenof receptors, increasing endogenous with the rise ligands, of scientific and a partial agonist of cannabinoid receptors type 1 (CB1) with metabolizing enzymes, makes important contributions higher affinity and is almost inactive against cannabinoid in physiological and pathological processes of the human receptors type 2 (CB2). AEA also activates transient receptor body [16]. Currently, there are many preclinical and clinical potential vanilloid receptor 1 (TRPV1) and the peroxisome studies indicating that cannabinoids have therapeutic phospholipaseproliferator-activated D and degraded receptor (PPAR).by fatty AEAacid isamide catalyzed hydrolase from potential in many diseases, such as nausea and vomiting N-acyl-phosphatidylethanolamine (NAPE) by NAPE-specific

into arachidonic acid and ethanolamine whereas 2-AG acts andassociated they witheven cancerdisplay chemotherapy, some anticancer intractable properties. childhood In eitheras a full DAG agonist lipase-alpha on both or CB1-beta, and and CB2 mostly with hydrolyzed moderate by to epilepsy, muscle spasms in patients with multiple sclerosis, low affinity. 2-AG is produced from diacylglycerol (DAG) by

Physicochemicalflowers [29]. Properties of THC and CBD: THC

(6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H- of C. sativa. THC has a molecular formula of C21H30O2 dibenzo[b,d]pyran-1-ol) is a major psychoactive cannabinoid colorless oil that has good solubility in several solvents, such with a molecular weight of 314.5 g/mol (Figure 2). THC is a

Figure 1: as ethanol, acetone, dimethyl sulfoxide (DMSO), chloroform, benzyl alcohol and sesame oil, but has a very low solubility Chemical structures of anandamide (A) and in water [31,32]. THC has a high boiling point at 157° C and a Phytocannabinoids:2-arachidonoylglycerol Phytocannabinoids (B). are a group of melting point less than 25° C [33,34]. plant-derived secondary metabolites. Phytocannabinoids CBD (2-[1R-3-methyl-6R-(1-methylethenyl)-2- cyclohexen-1-yl]-5-pentyl-1,3-benzenediol) has a low Echinacea purpurea, E. angustifolia, E. pallida, Acmella receptors. CBD has a molecular formula of C21H30O2 and a haveoleracea been, Helichrysum identified inumbraculigerum several plant, Radula species, marginata including psychoactive effect due to its low affinity to the cannabinoid and are mostly found in Cannabis sativa [25]. These Themolecular boiling weight points of CBD314.5 are g/mol, not clear, like butTHC are (Figure in the range2). CBD of receptors. The chemical structures of phytocannabinoids is crystalline solid and soluble in DMSO and°C [33,36].ethanol [35,35]. cannabinoids have an affinity to interact with the cannabinoid and monoterpene moieties. Currently, more than 100 160-180° C, and the melting point is 67.5 consist of lipid structure coupled withC. sativa alkylresorcinol. Cannabis cannabinoids are produced and accumulated as cannabinoid phytocannabinoids have been identified in acids, i.e. cannabigerolic acid (CBGA) and cannabigerovaric acid (CBGVA), and then enzymatically converted into their active metabolites, such as THC, CBD,Δ9-tetrahydrocannabivarin cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabinodiol cannabinoid(CBND), cannabinol synthase [26]. (CBN), (THCV), cannabivarin (CBV), and cannabidivarin (CBDV) by Cannabis sativa: Cannabis or hemp is plants in Cannabaceae Figure 2: family native to Central Asia. Cannabis is generally divided into 3 species, including C. sativa, C. indica, and C. ruderalis Chemical structures of Δ-9-tetrahydrocannabinol [27]. Biogenetic(A) and cannabidiol Pathway (B). of Cannabinoids: Cannabinoids is that cannabis is monotypic and consists only of a single speciesHowever, as C. sativa to date[28]. theC. sativa common is an scientificannual dioeciously emphasis anis aalkyl group chain, of terpenophenolicsolivetolic acid and that a monoterpene is comprised moiety, of two food, oil, and traditional medicine. The history of Cannabis in important parts, namely a diphenol (resorcin) carrying traditionalflowering plant medicines that has has long been been reported used as for a source5000 years of fibers, and geranyl pyrophosphate (GPP) [37]. Although there are THCmore and than CBD 60 [38]. cannabinoids Biosynthesis already of olivetolic found acid this is started review uses,is recommended including cancer for eczema,disease [29,30]. psoriasis, and inflammatory fromfocuses a conversion on the pathway of pyruvate, that leads a product to the from biosynthesis oxidation of diseases. Recently, it has been suggested for new therapeutic C. sativa contains several chemical compounds, such as isglucose subsequently in the glycolysis converted pathway, into malonyl-CoA to acetyl-CoA using by pyruvate acetyl- these, at least 100 are cannabinoids, a group of compounds dehydrogenase (PDH) or PDH bypass (Figure 3). Acetyl-CoA thatcannabinoids, have unique terpenoids, chemical structures flavonoids, [29]. and The alkaloids. plant produces Among hexanoyl-CoA, a medium-chain fatty acyl-CoA produced by all cannabinoids in their acidic forms and subsequently CoA carboxylase [37].n Another precursor in this pathway is

two steps. Firstly, -hexanol is generated by a breakdown of Suttithumsatid W and Panichayupakaranant P. Narrative Review: Phytocannabinoids and their Copyright© Suttithumsatid W and Panichayupakaranant P. Potential Use as a Phytochemotherapy. Int J Pharmacogn Chinese Med 2020, 4(3): 000209. 4 International Journal of Pharmacognosy & Chinese Medicine

C18 unsaturated fatty acids via using 3,5,7-trioxododecanoyl-CoA synthase or tetraketide or obtained by an early termination of the fatty acid biosynthesis. Then, the conversion the of n lipoxygenase-hexanol to hexanoyl- pathway Finally, olivetolic acid is formed via aldol cyclization of CoA is catalyzed by acyl-CoA synthetase [39]. Subsequently, 3,5,7-trioxododecanoyl-CoAsynthase (TKS) to produce using 3,5,7-trioxododecanoyl-CoA. olivetolic acid cyclase [37,40]. the condensation of malonyl-CoA with hexanoyl-CoA

Figure 3:

Biosynthesis of Δ-9-tetrahydrocannabinol and cannabidiol.

cannabinoid biosynthesis is produced via the condensation Isopentenyl pyrophosphate (IPP) and dimethylallylvia the of GPPCannabigerolic and olivetolic acid acid (CBGA), using the geranyl central pyrophosphate: precursor for pyrophosphate (DMAPP) are two important precursors The used in biosynthesis of geranyl pyrophosphate (GPP) converted into Δ-9-tetrahydrocannabinolic acid catalyzed2C-methyl-d-erythritol-4-phosphate by geranyl diphosphate synthase (MEP) [41]. pathway. olivetolate geranyltransferase (GOT). CBGA is subsequently head-to-tail condensation of IPP and DMAPP to form GPP is (THCA) and cannabidiolic acid (CBDA) by THCA synthase and Suttithumsatid W and Panichayupakaranant P. Narrative Review: Phytocannabinoids and their Copyright© Suttithumsatid W and Panichayupakaranant P. Potential Use as a Phytochemotherapy. Int J Pharmacogn Chinese Med 2020, 4(3): 000209. 5 International Journal of Pharmacognosy & Chinese Medicine cannabidiolic acid synthase, respectively. Finally, THCA and CBDA are decarboxylated to produce THC and CBD, μm respectively [29,37]. a Phenomenex Kinetex XB-C18 column (150 × 4.6 mm, 2.6 ) with a gradient elution, using 0.1% formic acid in water Quantitative HPLC Analysis of Cannabinoids validatedand acetonitrile using (withthe parameters, 0.1% formic including acid). A UVrecovery, detection bias, of intraday-all cannabinoids and interday-precision was set at 220 [45].nm. The method has been A simple reverse phase high performance liquid Brighenti et al. have reported another HPLC method determination of THC and CBD in an oromucosal spray made using a gradient elution system for analysis of four non- fromchromatography cannabis extract. (HPLC) This has method been involved developed the use for of the a psychoactive cannabinoids, namely CBDA, CBGA, CBG and CBD in C. sativa reverse phase Zorbax C-18 column (4.6 mm × 100 mm, 3.5 extracts. The analysis was performed using µm) isocatically eluted by a mixture of methanol and water a reversed phase HPLC method coupled with diode array (85:15 v/v) with a flow rate of 1.0 ml/min and a quantitative (UV/DAD) detection. The method involved the use of an throughdetermination linearity, wavelength accuracy, precision, of 220 nm. limits Both of THCdetection and CBDand Ascentis Express C18 column (150 mm × 3.0 mm, 2.7 µm) were eluted within 10 minutes. The method was validated eluted with a mixture of 0.1% formic acid in both water and that the method exhibited good linearity, accuracy, precision, acetonitrile, under a gradient elution system, with running quantitation and specificity parameters, and it was found CBDAtime of and 30 CBGA. minutes. The The method chromatograms has been successfully were detected validated at a wavelength of 210 nm for CBG and CBD, and at 220 nm for determinationsensitivity, specificity, of an amount and quantitation of THC and CBDlimits. [42]. This method [46]. shows a good separation and short run time (10 min) for for linearity, sensitivity, precision, accuracy, and specificity In addition, a simple isocratic HPLC method for analyzing Anticancer Effects of Cannabinoids THC, CBD and other cannabinoids in C. sativa and C. indica Receptors and Mechanisms of Anticancer plant powders andµm) their at extracts37°C, and has sample been reported.vials have Analyses been set The biological effects of cannabinoids are regulated by are performed using a Luna C18 column (octadecyl silica, 150 mm × 3 mm i.d., 3 at 10°C. The mobile phase consisted of water/acetonitrile at cannabinoid receptors. Recently, two major cannabinoid- 275a ratio nm. of This 9:31 method (v/v), with needed 0.1% a relativelyformic acid short (v/v) analysis and 10 time mM beenspecific described. receptors, Both namely CB1 and cannabinoid CB2 are G protein-coupled receptors type ammonium formate. The detection wavelength was set at receptors1 (CB1) andfamily cannabinoid [22,47]. Although receptors CB1 typeis mainly 2 (CB2) located have at including accuracy, precision, sensitivity, linearity, and various locations in the central nervous system, expression stability(8.5 min) [43]. and also exhibited a good analytical performance, of CB1 receptor is not limited to the central nervous

of body, including peripheral nervous system, liver, skeletal phase HPLC method for detection of ten cannabinoids from muscle,system. pancreas, It is widely and expressed adipocyte. in In many contrast, different CB2 is locations located Moreover, Mandrioli,C. sativa et al.. This have method reported is aperformed reversed- particularly in immune and blood cell systems, including macrophage, spleen, tonsils, thymus, and leukocyte [22,48]. the inflorescences of Action of THC depends on ability to activate the cannabinoid using a reverse phase column, Nex-Leaf CBX Potency (150 × receptors. THC is a partial agonist on both CB1 and CB2. 4.6 mm, 2.7 µm with a guard column Nex-Leaf CBX 5 × 4.6 mm, 2.7 µm) at 35° C, the autosampler set at 4° C, and the and acts as a potent antagonist for CB1 and CB2 [49]. In UV detection at 220 nm. The mobile phase A consisted of Conversely, CBD has low affinity for cannabinoid receptors underwater andgradient 0.085% elution. phosphoric The method acid, whilehas been the validatedmobile phase and types and different targets receptors of cannabinoids, i.e. exhibitedB composed good of results acetonitrile of validation and 0.085% parameters phosphoric including acid addition, CBD interacts with other cannabinoid receptor repeatability, reproducibility, recovery value, linearity, and peroxisome proliferator-activated receptors, transient sensitivity [44]. TRPV1, orphan G-protein coupled receptor 55 (GPR55),

Another reversed phase HPLC method has been bothreceptor CB1 potentialand CB2 resulting melastatin in inhibition 8 (TRPM8), adenylate and transient cyclase developed for determination of eight cannabinoids, receptor potential ankyrin 1 (TRPA1) [50,51]. Activation of with corresponding to inactivation of the protein kinase A THCA in C. sativa activated protein kinases. Furthermore, cannabinoids also including CBDV, CBDA, CBGA, CBG, CBD, CBN, THC, and phosphorylation pathway and activates several mitogen- samples. The method was performed using

phorbol myristate acetate could not prevent THC-induced role of cannabinoid system on carcinogenesis. Alteration of hydrolysis pathway, i.e. desipramine, scyphostatin and cannabinoidTo date, receptorthere are level still is conflicting an important data factors of an for important estimate THC and the selective inhibitors. In contrast, the inhibitors of the effects of endocannabinoids. The overexpressions of death of glioma cells when treatments of glioma cells with B1 could prevent THC-induced death of glioma cells. This cells, such as skin, prostate and colon cancer, hepatocellular impliedceramide that synthesis de novo pathway, i.e. L-cycloserine and fumonisin carcinoma,CB1 and CB2 endometrial have been sarcoma,shown in glioblastomavarious types multiforme, of cancers in cannabinoid-induced apoptosis of glioma cells [62]. An meningioma and pituitary adenoma, Hodgkin lymphoma, accretion of ceramide induces synthesized an activation ceramide of wasendoplasmic involved chemically induced hepatocellular carcinoma, mantel cell an upregulation of the expression of the stress-regulated proteinreticulum p8, stress-related a transcriptional signaling factor pathway that overexpress resulting in colorectallymphoma, cancer when and compared colon cancer with [55,56]. normal cells [53,54]. However, a low expression of CB1 was detected in metastatic i.e. transcription factor 4, C/EBP homologous protein, and Furthermore, raised concentration of endocannabinoids, various malignancies, together with its downstream targets, including anandamide and 2-arachidonoylglycerol have been reported in several types of cancer, especially in tribbles homolog 3 (TRIB3), which take part in control of glioblastoma, meningioma, pituitary adenoma, prostate and intumor turn development leads to an [63,64].inhibition Afterwards, of the mammalian activation targetof TRIB3 of causes inhibition of pro-survival protein kinase B (Akt) that translation of proteins, and eventually induced autophagy- levelscolon carcinoma,of cannabinoid and endometrialmetabolizing sarcoma enzymes [50,54]. and tumor Many mediatedrapamycin cell complex death 1[65,66]. (mTORC1), In addition taking to part glioma in activating cell, the aggressiveness.studies have exhibited Endocannabinoid the relationship degrading between enzymes expression is mechanism of the upregulation of protein p8 induced upregulated in aggressive human cancer cells and primary has been evidently exhibited in pancreatic and hepatic cancerautophagy cells pathway [67,68]. in the anti-tumor action of cannabinoids tumors. Accordingly, the tumor growth was decreased systemwhen the might endocannabinoid play an essential degrading role in cancer enzymes physiopathology expression [57-59].was knocked down. This suggests that an endocannabinoid Another probable mechanism of anticancer action of THC has been investigated in glioma cell. The cannabinoids in vitro and in vivo studies have indicated that cannabinoids can reduce and led to a depletion of Bcl-2-associated death promoter, Over the last few decades, numerous receptor agonist induced downregulation of Akt signaling mechanisms of endocannabinoids, the most prevalent anticancertumor growth effects and of cannabinoids progression. are Among the induction several of reported cancer resultinga proapoptotic in cancer Bcl-2 cell familyapoptosis member, [69]. which may play an cell death by apoptosis and the inhibition of cancer cell important role in downregulation of survival pathways, proliferation through regulation of the important signaling Furthermore, some additional mechanisms have been angiogenesis and block tumor invasion and metastasis in a death by THC. In hepatocellular carcinoma cells, THC reduced manypathways in vivo [60]. studies In addition, [54,60]. cannabinoids can decrease tumor theshown viability to provide of the humanthe process hepatocellular of an induction carcinoma of cancer cell lines cell by stimulation of CB2 receptors that bring on upregulation of Anticancer Activity of THC

There are abundant studies on antitumor activity of someTRIB3 evidence that cooperate supports with the the claim adenosine that calcium/calmodulin- monophosphate- activated kinase (AMPK) stimulation (Figure 4). In addition,β ceramideTHC focused synthesis on glioma de novo cells. THC has been shown as an dependent protein kinase kinase β (CaCMKK ) was lipidinduced molecules apoptosis that in consist glioma of cells sphingosine through and the a pathway fatty acid. of stimulationresponsible of for autophagy-mediated cannabinoid-induced cell AMPK death activation[68,70]. and (Figure 4). Ceramides are waxy subsequent inhibition of AKT–mTORC1 axis, resulting in the

A study on the antiproliferative mechanism of THC in human breast cancer cells has exhibited that THC activated decreased phosphorylation of the retinoblastoma protein, JunD, an activator protein-1 transcription factor that is anddependent eventually kinase cell 1 activation, cycle arrest which and lead apoptosis to the subsequent [71-73]. essential for cell proliferation in some cancer cells, by upregulating gene expression and translocating the protein factor induced phosphorylation of mitogen-activated protein Moreover, THC may act as an inhibitor of epidermal growth kinase inhibitor p27 and p21 and tumor suppressor gene cancers [74]. testinto the nuclearare the compartment JunD targets (Figure of THC 4). for The preventing cyclin-dependent cyclin- kinases and Akt to control the growth and metastasis of lung

Figure 4:

Some signaling pathways induced by THC in cancer cells. THC, Δ9-tetrahydrocannabinol; CB1, cannabinoid receptor 1; CB2, cannabinoid receptor 2; ER, endoplasmic reticulum; p8, protein p8; CHOP, C/EBP homologous protein; ATF4, activating transcription factor 4; TRIB3, tribbles homolog 3; Akt, protein kinase B; mTORC1, mammalian target of rapamycin C1; p21, cyclin-dependent kinase inhibitor 1; p27, cyclin-dependent kinase inhibitor 1B; TES, tumor suppressor gene testin; Cdc2-cyclin B, cyclin-dependent kinase 1; pRb, retinoblastoma protein; AMPK, adenosine monophosphate-activated kinase (AMPK); CaCMKKβ, calmodulin-activated kinase kinase β. Antitumor Activity of CBD mechanism of action mainly relies on the stimulation role on anticancer activity [75]. Recently, the proposed decreased cancer cell viability in many cancer types autophagy-mediated apoptosis [75,76]. In addition, CBD includingRecently, neuroblastoma, many studies glioblastoma, have revealed melanoma, that CBD of production of reactive oxygen species, which lead to leukemia, colorectal, breast, lung, and prostate cancer [50]. that lead to inhibition of hypoxia-inducible factor 1-alpha induced downregulation of ERK and Akt signaling pathway the mechanism of action of CBD is not related to a direct Regarding the potential effects of CBD on cancer treatment, in(HIF-1α) initiating has angiogenesis been reported and as regulating another mechanism cellular metabolism of action of CBD in human glioblastoma cells [77]. HIF-1α plays a role activation of the CB receptors (Figure 5). It has been reported and metastasis [78]. that interactions of CBD with other types of receptors to overcome hypoxia that lead to promoting tumor growth including GPR55, TRPV1 and TRPM8 may play an essential

Figure 5:

Some signaling pathways induced by CBD in cancer cells. CBD: Cannabidiol; TRPV1: Receptor potential channel subfamily V member 1; GPR55: Orphan G-protein coupled receptor 55; TRPM8: Transient receptor potential melastatin 8; ROS: Reactive oxygen species; HIH-1: Hypoxia-inducible factor 1-alpha. Inhibition of Angiogenesis and Metastasis

thereduced expression the expression of cyclin-dependent of the VEGF andkinase VEGFR. inhibitor Moreover, p27, tumor progression at various levels. The induction of anotherthe cannabinoid protein advocated receptor to agonists play a role were as a able proangiogenic to inhibit cancerCannabinoids cell death by inhibited apoptosis tumor and cellthe inhibition growth and of impaircancer cell proliferation are the most common mechanism of cancer cells to lymph nodes [82,83]. In addition, it has beenfactor demonstrated that correlated that with the an cannabinoidincreased spreading receptor of agonists thyroid cannabinoids also impair tumor angiogenesis and block inhibited cancer cell proliferation and metastasis in other invasioncannabinoids. and metastasis In addition, in manya variety studies of models have shown of cancer, that mechanisms, including modulating the cyclooxygenase-2/ i.e. gliomas, skin cancer, thyroid cancer, and breast cancer [50,79]. [84].prostaglandin E2 signaling pathway by inhibiting the activity Based on in vitro and in vivo studies, THC inhibited of the downstream molecules such as c-Fos, c-Jun, and Cdc42 tumor angiogenesis by inhibition of ceramide biosynthesis and metastasis of some cancer cells by acting separately fromIn the contrast, cannabinoid CBD has beenreceptors. shown In to breastexhibit angiogenesiscancer, CBD that lead to inhibition of vascular endothelial growth factor (VEGF) production and VEGF receptor (VEGFR)-2 activation. These changes in the VEGF pathway were coordinated with a factordownregulated of the metastatic Id-1 (helix-loop-helix potential of breast transcription cancer that involved factor throughdecrease the in size process of gliomas of impairment [80]. Likewise, of tumor in skinvascularization, tumors, the ininhibitor neovascularization of DNA binding [85]. 1) In gene addition, expression, CBD can an lead essential to a ascannabinoid determined receptor by agonistsdisrupted showed vessel an antitumorstructure effectand decrease in lung tumor cell invasion and metastasis through a mechanism relied on the upregulation of the intercellular

Similarly,downregulated the cannabinoid expression ofreceptor proangiogenic agonists factors, also inhibited namely endothelial cells and cells of the immune system. An increase VEGF, placental growth factor, and angiopoietin 2 [81]. adhesion molecule 1 (ICAM-1), a protein that expressed on the growth of thyroid carcinoma cells in mice as well as of ICAM-1 has been related to the upregulation of tissue

Suttithumsatid W and Panichayupakaranant P. Narrative Review: Phytocannabinoids and their Copyright© Suttithumsatid W and Panichayupakaranant P. Potential Use as a Phytochemotherapy. Int J Pharmacogn Chinese Med 2020, 4(3): 000209. 9 International Journal of Pharmacognosy & Chinese Medicine inhibitor of matrix metalloproteinases-1, a glycoprotein that Toxicity Assessment of Cannabinoids may have an anti-apoptotic function [86]. A recent study has and inhibit metastasis on colon cancer, glioma, and prostate cannabis is used for recreational purposes because there cancerexhibited [87]. that CBD significantly reduced VEGF expression is noThe clear toxic demonstration evidence of cannabinoidsof doses that oftenachieve shows symptoms when desired by a cannabis user. In adolescents and adults, inhaled Pharmacokinetics of Cannabinoids doses of 2 to 3 mg of THC and oral administration doses of 5 to 20 mg THC can lead to impaired attention, concentration, short-term memory loss and executive functioning [97]. distribution, metabolism, and excretion of a drug from human body.The Generally, acronym the ADME pharmacokinetics is used to describe of cannabinoids absorption, is hypotension, delirium, panic attacks, anxiety, and myoclonic varied by the routes of administration [88]. THC and CBD More serious adverse effects, including nausea, postural are highly lipophilic compounds and rapidly absorbed by the lungs resulted in an increased maximum plasma concentratedjerking, may occur cannabis when products high doses [99]. of THC are administered [98]. Psychosis has also been related with a use of higher after administration by smoking, inhalation, or intravenous CBD is also not risk-free. The adverse effects of CBD route.concentration Pulmonary (Cmax) administration of THC and route CBD of and THC reached resulted faster in a including developmental toxicity, embryo-fetal mortality, central nervous system inhibition and neurotoxicity, maximum blood concentration within minutes. In contrast, the oral bioavailability of THC and CBD is low. The absorption hepatocellular injuries, spermatogenesisin vivo reduction,, at doses higher organ calorierate is meals lower [89,90]. in oral In administration. addition, it has However, been found their that Cmax time thanweight recommendation alterations, male for human reproductive pharmacotherapies. system alterations, Some are increased after oral administration with high fat or high clinicaland hypotension studies have have reported been shown that CBD can induce hepatic and not a dose-dependent kinetic [91,92]. abnormalities, diarrhea, fatigue, vomiting, and somnolence to the Cmax of CBD was mostly shown between 1 and 4 hours [100]. The distribution of cannabinoids in the body is depended on their lipophilicity and solubility. THC and CBD are Conclusion Cannabinoids are a large and important group of extremely lipophilic, which imply that they are highly protein secondary metabolites found in C. sativa that tend to have bound (94 to 99%). THC has a volume of distribution of 10 L/ therapeutic potential for the treatment of variety of diseases, kg, whileBecause that of of theCBD high is 32 lipophilicity L/kg [93-95]. of cannabinoids, they are needed to metabolize to increase hydrophilicity before excretion. The cannabinoids are mainly metabolized via inincluding the control cancer. of cancer Cannabinoids cell survival, were in able both to in effectively vitro and inhibit in vivo tumor growth by modulation of the signaling pathways crucial for antitumor effects are induction of apoptosis and the andhepatic 3A4. cytochrome Besides the oxidases liver, other enzyme. tissues Metabolism such as heart of THCand experiments. The two major mechanisms of cannabinoids lungoccurs can principally metabolize by cannabinoids,hepatic cytochrome but to P450a lesser (CYP) amount. 2C19 of tumor angiogenesis, invasion, and metastasis. C. sativa Biotransformation of THC produces mono-, di-, and tri- producesinhibition more of cancer than cell100 proliferationdifferent cannabinoids, as well as inhibitionincluding hydroxy metabolites and the inactivated metabolite is THC- THC and CBD. THC mainly exhibit antitumor effects via CB1 carboxylase [88,89,96]. Similarly, CBD is also metabolized via and CB2 dependent stimulation of the de novo synthesis. On hepatic and gut by CYP2C19, CYP3A4, UGT1A7, UGT1A9, and the other hand, CBD acts independently of the CB1 and CB2, UGT2B7 to the primary active hydroxy metabolites, and then to be an inactive metabolite by CBD-carboxylase [92,93]. by interactions with other types of receptors (GPR55, TRPV1, THC is mostly excreted mainly as the acid metabolites in TRPM8). However, there is still a lack of high quality of safety inand human. efficacy The clinical uses trials.of cannabinoids Therefore, itin iscancer very difficulttreatment to assess the potential benefits and risk of using cannabinoids lipidurine storage(20-35%) compartments and feces (65-80%) and enterohepatic within days andcirculation weeks. other drugs/food supplement, or assessing adverse effects. Based on lipophilic property, THC is slowly release from Currently,still needs the elucidation use of cannabinoids such as dosages, as a treatment interactions for cancer with highand makes percentage its elimination of CBD inactive half-life metabolites to be slow are(25-36 excreted hours). in potential of cannabinoids is being conducted to support their theUnlike feces THC, and aminor major in part urine. of The CBD elimination is excreted half-life unchanged. of CBD A evidencestill has a for long the way anticancer to go. However, treatment. research on anticancer is around 18-32 hours [92].

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