Review ArticleNoscapine, an Emerging Medication for Different Diseases:A Mechanistic Review

Pouria Rahmanian-Devin,1,2 Vafa Baradaran Rahimi,2 Mahmoud Reza Jaafari,3,4

Shiva Golmohammadzadeh,3,4 Zahra Sanei-far,5 and Vahid Reza Askari 5,6,7

1Department of Pharmaceutics, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran2Department of Cardiovascular Diseases, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran3Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University ofMedical Sciences, Mashhad, Iran4Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran5Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran6Department of Pharmaceutical Sciences in Persian Medicine, School of Persian and Complementary Medicine,Mashhad University of Medical Sciences, Mashhad, Iran7Department of Persian Medicine, School of Persian and Complementary Medicine, Mashhad University of Medical Sciences,Mashhad, Iran

Correspondence should be addressed to Vahid Reza Askari; askariv@mums.ac.ir

Received 19 August 2021; Revised 8 October 2021; Accepted 15 November 2021; Published 29 November 2021

Academic Editor: Songwen Tan

Copyright © 2021 Pouria Rahmanian-Devin et al. .is is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in anymedium, provided the original work isproperly cited.

Noscapine is a benzylisoquinoline alkaloid isolated from poppy extract, used as an antitussive since the 1950s, and has no addictiveor euphoric effects. Various studies have shown that noscapine has excellent anti-inflammatory effects and potentiates theantioxidant defences by inhibiting nitric oxide (NO) metabolites and reactive oxygen species (ROS) levels and increasing totalglutathione (GSH). Furthermore, noscapine has indicated antiangiogenic and antimetastatic effects. Noscapine induces apoptosisin many cancerous cell types and provides favourable antitumour activities and inhibitory cell proliferation in solid tumours, evendrug-resistant strains, via mitochondrial pathways. Moreover, this compound attenuates the dynamic properties of microtubulesand arrests the cell cycle in the G2/M phase. Noscapine can reduce endothelial cell migration in the brain by inhibiting endothelialcell activator interleukin 8 (IL-8). In fact, this study aimed to elaborate on the possible mechanisms of noscapine againstdifferent disorders.

1. Introduction

With the chemical formula C22H23NO7, noscapine is abenzylisoquinoline alkaloid compound found in Papaver-aceae, Berberidaceae, and Ranunculaceae [1]. Althoughnoscapine is extracted from alkaloid-rich plants, such aspapaverine, it has none to mild effects on central nervoussystem (CNS) activities and does not cause respiratorysuppression, euphoric, or addictive effects [2]. Initially,noscapine was considered and used clinically for its anti-tussive effects [3] and has shown minimal toxic effects inanimals and humans [4]. Due to the lack of opioid effects,noscapine is a safe alternative to codeine and

dextromethorphan for treating cough. Likewise, in theNetherlands, noscapine is considered the first-choicemedicine for treating paediatric cough [5].

In the recent decade, various pharmacological propertieshave been expressed for noscapine, including inducingapoptosis in cancer cell lines and inhibiting tumour cellgrowth [6]. It has also been observed that noscapine caninhibit the bradykinin receptors in both in vitro and in vivoexperiments [7, 8]. Furthermore, noscapine derivatives arestructurally similar to colchicine in that both contain adimethoxy phenyl group, which can act on its receptors andhave similar effects to colchicine. Also, studies show thatnoscapine and its derivatives reduce the dynamics of

HindawiEvidence-Based Complementary and Alternative MedicineVolume 2021, Article ID 8402517, 16 pageshttps://doi.org/10.1155/2021/8402517

microtubules by increasing the stopping time of microtu-bules [9]. Clinically, lack of systemic and histological tox-icity, favourable oral bioavailability and pharmacokinetics(clearance about 10 hours), and appropriate tumour-tar-geting activities are deliberated good characteristics ofnoscapine [10]. .erefore, this study aimed to review thebiopharmacy and pharmacokinetics anti-inflammatory,antioxidant, and anticancer effects of noscapine by focusingon its receptors and signalling pathways.

2. Methods

Scientific databases, including Web of Science, PubMed,Scopus, and Google Scholar, were searched in English untilthe end of July 2021. .e search terms were critical words,including “immunomodulation”, “anti-inflammatory” OR“immune system” OR “inflammation” OR “cancer” OR“tumour” OR “oxidative stress” OR “P-glycoprotein (P-gp)”OR “cell toxicity” OR “anti-mitotic”, OR “benzylisoquino-line alkaloid” AND “noscapine”, “Opiate”, “Papaveraceae”,and their combinations. All in vitro and in vivo studies andclinical trials examining the biopharmacy and pharmaco-kinetics anti-inflammatory and anticancer effects ofnoscapine were included. Unpublished data, “letters to theeditor”, and non-English articles were also excluded. Wehave reviewed about 472 research articles, and finally, theresults of 67 articles were evaluated and scrutinised for thepresent review study.

3. Results

3.1. Biopharmacy and Pharmacokinetics of Noscapine

3.1.1. Physical and Chemical Characteristics. After mor-phine, noscapine is the most abundant alkaloid in thePapaver somniferum [11]. .e French chemist CharlesDerosne isolated noscapine from opium in 1803 andnamed it “sel narcotique de Derosne” [1]. Noscapine has amolecular weight of 413.42 g/mol, and its molecular for-mula is C22H23NO7. It is a polar molecule with a meltingpoint of 176°C and 1.395 g/mL density. It is a white powderthat has a bitter taste and is odourless. Noscapine is almostinsoluble in water (0.181mg/ml), most soluble in vegetableoils (Log P � 2.58), slightly soluble in alcohol and ether,and soluble in benzene and acetone [1, 12]. However,noscapine hydrochloride is freely soluble in water andethanol (∼750 g/ml) [12]. In addition, noscapine has astable metabolite called meconin, which is excreted in theurine and dissolves in water at an amount of 2.5mg/mL at25°C. .is metabolite is a skin irritant [1]. Noscapine cancross the blood-brain barrier very quickly due to its highlipophilic properties [1, 12].

3.1.2. Pharmacokinetics in Experimental Animals. In micepharmacokinetics models, noscapine was administratedintravenous bolus at 10mg/kg and orally at 75, 150, and300mg/kg and then extracted from the plasma by theprotein-precipitation method [13]. Following 10mg/kgintravenous dose, the average plasma concentration of

7.88 μg/ml within 5 minutes after injection and declinedwith undetectable levels at 4 h. .e mean of total bodyclearance and mean volume of distribution (V (d)) were4.78 L/h and 5.05 l, respectively. Using the non-compartmental analysis, the mean area under the plasmaconcentration-time curve (AUC) for noscapine was 53.42,64.08, and 198.35 h μg/mL reaching maximum plasmaconcentrations (C (max)) of 12.74, 23.24, and 46.73 μg/mLat a t (max) of 1.12, 1.50, and 0.46 h at the linearly in-creasing dose levels [13].

3.1.3. Pharmacokinetics in Human. In humans, it has beenshown that oral administration of 50mg noscapine results inrapid absorption and a plasma concentration of 182 ng/mL,one hour after administration. Following the absorption,noscapine levels are reduced by 30%, with a half-life of 124minutes and an absolute oral bioavailability [14]. Four hoursafter administering noscapine, its blood concentration levelis undetectable, indicating an average total body clearance of4.78 L/h with an average distribution volume of 5.05 L.

3.1.4. Side Effects of Noscapine. A study in 1961 on cancerpatients reported that 80% of patients showed no side effectswhen taking daily doses of up to 3 g/day, while the remaining20% felt drowsy and pain in the belly. However, adminis-tration of 4–6 grams orally daily may cause headache,dizziness, and even coma [11, 15].

3.2. Anti-Inflammatory Effects. Inflammation is a complexprocess that protects tissues against various injuries in aparticular way and is a controlled outcome between in-flammatory and anti-inflammatory agents. Chronic in-flammation occurs when the inflammation goes out ofphysiological condition. .ese conditions are seen in somediseases such as metabolic syndrome, rheumatoid arthritis,psoriasis, osteoarthritis, and cancer [16–20]. Eventually,chronic inflammation causes inflammatory disorders andpain through the secretion of inflammatory mediators, in-cluding prostaglandins, nitric oxide (NO), interferon c

(IFN-c), and histamine [21].Interestingly, various studies have indicated that

noscapine has anti-inflammatory effects and significantlyreduces the levels of proinflammatory factors such as in-terleukin 1β (IL-1β), IFN-c, and IL-6. In this regard, inanother study, Khakpour et al. examined the effect ofnoscapine against carrageenan-induced inflammation inrats. .ey found that noscapine at a dose of 5mg/kg bodyweight in three hours after the injection has the most anti-inflammatory effects. Moreover, they showed that theamount of inflammation reduction at this dose of noscapineis approximately equal to the indomethacin as a known andstandard anti-inflammatory medication [22, 23]. Further-more, Shiri et al. concluded that noscapine prevented theprogression of bradykinin-induced inflammation in the rat’sfoot by antagonising bradykinin receptors [22].

In addition, Zughaier et al. evaluated the anti-inflam-matory effects of brominated noscapine. .e brominated

2 Evidence-Based Complementary and Alternative Medicine

form of noscapine has been shown to inhibit the secretion ofthe cytokine TNF-α and the chemokine IP-10/CXCL10 frommacrophages, thereby reducing inflammation without af-fecting macrophage survival [24]. Furthermore, the bro-mated derivative of noscapine has about 5 to 40 times morepotent effects than noscapine [25]. Again, this brominatedderivative also inhibits toll-like receptor (TLR), tumournecrosis factor α (TNF-α), and NO in human and mousemacrophages without causing toxicity [26]. Furthermore,brominated noscapine has potent anti-inflammatory activityin models of septic inflammation, inhibits inflammatoryfactors in a dose-dependent manner, and prevents the re-lease of TNF-α and NO in human and mouse macrophages[27].

Another study on inflammatory bowel disease (ulcera-tive colitis) and colon cancer found that noscapine had anexcellent anti-inflammatory effect that could significantlydecrease the levels of proinflammatory factors such as IL-1β,IFN-c, and IL-6, compared to the control group [26]. Ad-ditionally, it has been found that chitosan nanoparticlescontaining brominated noscapine derivatives could reduceproinflammatory cytokines such as IL-1β, IFN-c, and IL-6and inflammation within colon mucosal tissue [26].

3.3. Anticancer Effects. Studies have shown that noscapineinhibits cell proliferation in many cancer cells, even manydrug-resistant strains, and does not affect healthy cells.Compounds that have inhibitory effects on microtubulesactivate the mitosis phase control station and arrest the cellcycle, thus maintaining the balance between the monomerand the tubulin polymer, the tubulin polymerising morethan usual. Various studies have shown that noscapine hasan inhibitory effect on the skin, ovarian, blood, breast, andglioblastoma cancers without causing dose-dependent tox-icity to the tissues of the kidney, heart, liver, bone marrow,spleen, and small intestine [1].

Collectively, two mechanisms for effects of noscapineanticancer are suggested, including downregulation of HIF-1 (hypoxia-inducible factor-1) and VEGF expression[28, 29], which are essential for the formation of bloodvessels [30]. .e secondary mechanism is also antimitoticeffects by its inhibitory effects on microtubules [31].However, relatively high doses of noscapine(ED50� 300mg/kg) are necessary to induce anticancer ac-tivity [32].

Antimitotic effects of noscapine provide it as an at-tractive anticancer medicine or lead compound for manyresearchers [31]. However, noscapine targets microtu-bules and destabilises their dynamics. While it does notalter the microtubule arrangement of healthy cells,mammalian cells are disrupted during the mitotic phase ofcell division, leading to programmed cell death [33]. Inaddition, although other drugs, such as colchicine andpaclitaxel, also affect tubulin, noscapine binds to differentsites of tubulin due to structural differences from othermedications [34]. Due to its antimitotic effects, noscapinehas been found in various cancers such as lymphoma,melanoma, breast, ovarian, and bladder cancers [31].

Quisbert-Valenzuela et al. showed that noscapine has aselective apoptotic effect on different breast cancer celllines, attributed to the inactivation of NF-κβ and activatesapoptotic pathways [35].

3.3.1. Breast Cancer. For example, Chougule et al. [36]found that noscapine exerts its antitumor effect in a dose-dependent manner. .erefore, they applied an oral dose of550mg/kg of noscapine alone and oral administration of300mg/kg/day combined with intravenous administrationof doxorubicin (DOX, 1.5mg/kg) on the MDA-MB-231breast cancer tumours xenograft model [36]. It has beenobserved that administration of low concentrations ofnoscapine has improved the antitumor activity of DOX bythree times in triple-negative breast cancer. In an additionalexperiment, noscapine with a concentration of approxi-mately 36 μM (IC50� 36 µM) can inhibit the proliferation ofbreast cancer cells [36].

A noscapine derivative called NPN (VinPhe-Nos) hasgreat potential in treating invasive cancers by severelyinhibiting new colonies and arresting the cell cycle in the G2/M phase and the S phase [37, 38]. In addition, studies haveshown that the noscapine NPN derivatives can bind totubulins and disrupt the tertiary structure of the protein[39]. .is study also showed that NPN structurally alteredtubulin protein and increased colchicine binding to tubulin[39]. Noscapine causes only minor damage to cell micro-tubules, but NPN severely damages microtubules, alteringtheir arrangement and preventing them from rearranging[40].

3.3.2. Lung Cancer. In one study, it has been demonstratedthat the combination of noscapine 300mg/kg/day orally andgemcitabine (30mg/kg) inhibited lung tumour growth by an82.9% rate. However, using each treatment, gemcitabine andnoscapine alone could inhibit the tumour growth of non-small-cell lung cancer cells by 39.4% and 34.2%, respectively[32]. .us, it indicates the synergism effect of noscapine ongemcitabine against non-small-cell lung cancer.

3.3.3. Glioblastoma. Temozolomide (TMZ) is a chemo-therapeutic agent used for glioblastoma that works byalkylating DNA and targeting proliferation [30]. Resistanceto temozolomide involves several mechanisms, including thehigh activity of DNA-repairing enzyme (methylguaninemethyltransferase) (MGMT) and the broad expression ofantiapoptotic proteins and P-glycoprotein (P-gp) pumps[30].

Interestingly, it has been reported that noscapine alonecould inhibit the proliferation of temozolomide-resistantglioblastoma cell lines [30]. However, studies show that theconcentration of noscapine required to inhibit the growth oftemozolomide-resistant glioblastoma cells, which is not veryhigh (20–75 µM) [41], but noscapine has significantly in-creased animal survival [30]. In addition, combinationtherapy of noscapine with temozolomide and cisplatin inxenografts significantly increased the efficacy of these drugs

Evidence-Based Complementary and Alternative Medicine 3

without showing any particular toxicity. Moreover, this invitro combination therapy reduced cell proliferation andincreased apoptosis in a tumour [41].

Although noscapine has low toxicity and desirableproperties, it requires higher doses for providing anticancereffects, preventing noscapine from progressing in thepharmaceutical market. Numerous formulations have beendeveloped, such as the preparation of nanoparticles [4, 42]and the water-soluble complex [43], but research is ongoingto address its pharmacokinetic limitations. .e slow-releaseformulation of noscapine can provide a good plasma con-centration of noscapine over a more extended period, whichcan help treat cancer [44].

In one study, the effect of noscapine solidified lipidnanoparticles on glioblastoma cells was investigated. .esize obtained (101± 4.8 nm) for noscapine nanoparticlescould be suitable for accumulation in tumour tissue byincreasing penetration into the tissue and more lasting ef-fects within the tissue [45]. In addition, these nanoparticlesreduced side effects. However, it has been found that thecytotoxicity of noscapine IC50 nanoparticles is significantlyhigher than noscapine hydrochloride. In contrast, PEGy-lated lipid nanoparticles containing noscapine IC50 haveless cytotoxicity than the free form of noscapine [46].Furthermore, an examination of noscapine-containingPEGylated gelatin nanoparticles on glioblastoma cellsshowed that noscapine hydrochloride provided less cyto-toxicity in the breast cancer cell line [47].

3.3.4. Ovarian Cancer. A noscapine derivative called 9-ni-tro-noscapine has the effect of selectively binding to theovulation of human ovarian cancer cells and human lym-phoblastoid cells while not affecting the normal human cellcycle [48].

3.3.5. Colon Cancer. A study also found that noscapineactivated PI3K/mTOR signalling and reduced PTEN ex-pression in LOVO 5FU and HT29/5FU cancer cells. Inaddition, it was found that noscapine significantly inducesapoptosis of human colon cancer cells HT29/5FU andLOVO/5FU, indicating that it acts as an anticancer agent fortreating colon cancer [49, 50].

.e mechanism of drug resistance of cancer cells is thatenzymes that directly regulate glycolysis and phenotypes areeffective in drug resistance. .erefore, targeting criticalmetabolic enzymes can have a therapeutic effect by in-creasing drug-induced apoptosis in cancer cells [51].According to the results, inhibition of the Warburg effectmay increase the sensitivity of HT29/5FU and LOVO/5FUcells to noscapine. .erefore, it is estimated that targetingthe development of Warburg improves the response tocancer cell therapy, and the combination of targeted drugswith inhibitors of cellular metabolism may be a promisingstrategy to enhance drug resistance in cancer.

3.3.6. Osteosarcoma. One of the critical steps in cancerinvasion andmetastasis is the destruction of the extracellular

matrix. MMP2 plays an essential role in the destruction ofthe extracellular matrix [52]. Noscapine in MG63 cellscauses downregulation of MMP2 and simultaneously in-hibits the EGFR pathway [53].

4. Targets of Noscapine, Receptors, andSignalling Pathways

4.1. Effects of Noscapine on Autophagy. Autophagy is aknown cell pathway that removes macromolecules anddestroys defective cytoplasmic components. According toprevious studies, autophagy is directly related to vacuolationin the cytoplasm and the rearrangement of microtubulelight-chain proteins. .e rearrangement of microtubulelight-chain proteins plays a role in the structure of auto-phagic vesicles. Recent reports indicated that autophagy isdirectly involved in controlling inflammatory responses[54]. Noscapine analogues significantly induced autophagywhen in contact with macrophages. In fact, it has beenobserved in a study that inhibition of autophagy by 3-methyladenine (3-MA) reduced the anti-inflammatory ac-tivity of noscapine analogues. .us, induction of autophagy,to some extent, is associated with the anti-inflammatoryactivity of noscapine and its derivatives [24]. It possiblyinterferes with the depletion of cytosolic signals by reducingthe dynamics of microtubules, thereby reducing inflam-matory responses.

Various studies have shown that ROS is also involvedin the development of autophagy [55]. However, the re-lationship between apoptosis and autophagy is complex.Under certain conditions, autophagy selects adaptation tostress and prevents cell death. In other cases, autophagy isan alternative pathway to cell death. .is evidence sug-gests that noscapine and its derivatives have anti-in-flammatory activity without toxic effects on the cell.Furthermore, noscapine and its derivatives inhibit thetransmission of cellular signals or delay transcriptionthrough proteins by acting on tubulin and reducing theirdynamics [24].

4.2. Effects of Noscapine on PTEN Tumour Suppressors.PTEN tumour suppressors have been observed frequently inmany human cancers, including mutated colon cancer. Inparticular, dephosphorylation of 3-phosphate catalyses theInositol ring in PTP3, thereby inhibiting PIP2 bisphosphate,and inhibiting PI3K phosphorylation, thereby inhibitingAKT and kinase activity, leading to apoptosis [56]. Con-versely, shutting down PTEN activates the PI3K/AKT sig-nalling pathway, resulting in tumorigenesis [57].

Studies have shown that PTEN expression is induced inHT29/5FU and LOVO/5FU cells. Noscapine and PTENinterference with PI3K/mTOR activation reverses the effectof noscapine on cell apoptosis. Conversely, mutation of thePTEN gene can lead to abnormal PIP3 activation andprevent cell death. According to previous studies, P-ex-pression PI3K and PmTOR were significantly increased innoscapine-treated HT29/5FU and LOVO/5FU cells aftertransfection with si-PTEN. Eventually, noscapine regulates

4 Evidence-Based Complementary and Alternative Medicine

mitochondrial damage, and the Warburg effect via PTENinduces apoptosis of colorectal cancer cells HT29/5FU andLOVO/5FU, and this mechanism is closely related to thePI3K/mTOR signal (Table 1) [56].

4.3. Effects of Noscapine on Bradykinin Receptors. .e kininsystem is one of the plasma protein systems involved incausing inflammatory reactions.

Bradykinin (BK), as the essential product of this system,along with other inflammatory mediators, including ei-cosanoids, histamine, oxygen-free radicals, and substance P,initiates inflammatory reactions, the activity of neurons inthe pain pathway, and the onset of oedema in the affectedarea and damaging the blood-brain barrier [58–60].

Bradykinin is also responsible for the vasodilationcaused by nitric oxide in smooth muscle [61].

.e kallikrein-kinin system (KKS) is activated duringinflammatory processes. Bradykinin (BK), calidin (Lys-BK),and their C-terminal metabolites increase vascular perme-ability, vasodilation, and expression of proinflammatorycytokines [61]. .ese effects are mediated by two receptors:the bradykinin B1 receptor and the B2 receptor. Usually, theB1 receptor is not present in healthy tissue; however, it isproduced by tissue damage and proinflammatory cytokinesthrough NF-κB activation. Activation of B1 receptors in-creases vascular permeability, leukocyte adhesion, and ex-pression of proinflammatory molecules such as vascularendothelial growth factor A (VEGF-A), VEGF-R2, ICAM-1,VCAM1, COX-2, and IL-1β in the diabetic retina [58–60].

Additionally, the BK induces angiogenesis by regulatingbasal FGF regulation (bFGF) through B1 receptors and bystimulating VEGF formation through B2 receptors in anabsent vascular model. B1 receptors enhance compensatoryangiogenesis in mouse models of obstructive vascular dis-ease, and activation of these receptors also promotes theproliferation and survival of endothelial cells, while B1 re-ceptor antagonists induce apoptosis [62].

4.3.1. Ischemic Injuries. In ischemic injury of various organs,bradykinin B1 and B2 receptors are affected [58]. B2 re-ceptors are expressed in the nervous system, while B1 isinduced in response to inflammatory cytokines [63]. Acti-vation of B2 receptors generates free radicals following is-chemic damage in rats and impairs brain function [63].

Noscapine noncompetitively antagonises bradykininreceptors, crosses the blood-brain barrier easily, and targetsthe ischemic region of the brain for damage due to itsprotective and anti-inflammatory to reduce effects ner-vousness [8, 64]. Cytotoxic free radicals and released neu-rotransmitters, such as bradykinin, are involved in thepathogenesis of ischemic brain injury [65].

As a noncompetitive antagonist of bradykinin receptors,noscapine has been shown to protect against brain damageby reducing oedema against hypoxia/ischemia in neonatalmice. Also, it reduces damage to muscle activity [66]. Also,noscapine reduces cell death through various mechanisms,including inhibition of oxidative stress and reduced neu-trophil permeability. It also reduces the permeability of

vascular endothelium to nerve damage [58]. In addition, itincreases reperfusion to the area of ischemic injury [8].

In a clinical study, oral administration of noscapine(50mg/day for five days) to patients (hypoxic-ischemic)improves the clinical prognosis and significantly reducesmortality [67]. Moreover, in another clinical trial, oral ad-ministration of noscapine improved prognosis and reducedmortality in stroke patients, but the exact mechanism ofaction is still unclear [8].

Bradykinin receptor antagonists show protective effectsin various tissue ischemia/reperfusion injury models, es-pecially in the brain and kidneys [68].

4.3.2. Cough. Noscapine has been shown to suppress coughinduced by enalapril and FR19099F (a nonpeptide B2 re-ceptor agonist) in guinea pigs, whereas it was not improvedwith naloxone premedication (a specific opioid antagonist)[69]. .e findings showed that opioid receptors do notmediate the antitussive effects of noscapine. Accumulationof bradykinin has been suggested as an essential mechanismof cough induction by angiotensin-converting enzyme(ACE) inhibitors [70]. Mooraki et al., in 90% of patients withhypertension, stated that noscapine could suppress thecough caused by ACE inhibitors. Interestingly, some of thesepatients received lower doses of antihypertensive drugs withnoscapine [7].

4.4. Effects of Noscapine on Tubulin. Drugs that act on mi-crotubules, such as taxol derivatives and vinca alkaloids, arepowerful anticancer drugs used in various cancers. However,these drugs are expensive to use due to limitations such aslow solubility. Also, due to their nonselective action, thesedrugs have toxicities such as peripheral neuropathy, gas-trointestinal toxicity, myelosuppression, and immune sup-pression [25]. Nevertheless, the FDA approved taxols in1996 for breast and ovarian cancer [71]. .e efficacy of taxolin treating invasive breast and ovarian cancer is an incentiveto identify newer compounds that target microtubules butare less toxic than these compounds.

New compounds that target microtubules must havedesirable properties, such as high water solubility, the abilityto be taken orally, and the establishment of appropriateblood concentrations after consumption. In addition, thesecompounds can have a synergistic effect on the commondrugs used in low amounts like taxols.

Noscapine is one of the compounds that is rapidlyabsorbed orally by the body and affects tubulin [14].Noscapine binds to tubulin and disrupts the cell cycle bydisrupting the ability of microtubules to accumulate.However, unlike most antitubulin agents, noscapine doesnot significantly alter the polymer mass of microtubules anddoes not cause severe damage to microtubules [72]. Instead,noscapine works by making minor changes in the accu-mulation and dynamics of microtubules [40]. Dynamicpolymerisation and depolymerisation of microtubules toform mitotic spindles are an essential step in cell prolifer-ation. .is feature modulates the dynamics of microtubulesand prevents cancer cell mitosis. .us, noscapine works

Evidence-Based Complementary and Alternative Medicine 5

differently from the current anticancer drugs such as taxolsand vinca alkaloids. Noscapine does not alter the arrange-ment of microtubules but reduces the dynamics of micro-tubules to activate mitotic activation sites [14].

Noscapine has been shown to bind to tubulin and stoptubules in the G2/M stage of mitosis. Also, noscapine doesnot alter the polymer-to-monomer ratio, unlike existingmicrotubule drugs that overpolymerise or destroy micro-tubules (such as taxols and vinca alkaloids) [77]..erefore, itdoes not cause any blood or nerve poisoning [73]. Noscapinederivatives bind to tubules with greater affinity; however,these derivatives prevent cell proliferation and induce ap-optosis death in human cancer cells [74]. Noscapine and itsderivatives have been predicted to bind to tubules α and β ofheterodimers near the colchicine binding site. However, theydo not interfere with the binding of colchicine to its location[75].

Moreover, noscapine and two taxols (paclitaxel anddocetaxel) bind to tubulin at different sites [76]. .us,noscapine binds to the α and β sites of tubulin, but the twotaxols attach to the b site [77, 78]. In fact, it suggests thatnoscapine may have a synergistic effect on tubulininhibitors.

Despite the relatively low toxicity of noscapine, theanticancer activity of noscapine has been reported in themicromolar range. As a result, studies were done on itsstructure to produce compounds with greater strength.Further investigation of the mechanisms of noscapinerevealed that this alkaloid increases the acetylation pattern ofmicrotubules. Acetylated microtubules generally do notshow sufficient dynamics [79]. Noscapine NPN derivativeseverely disrupts the network of microtubules, prevents theirreassembly, and decreases the dynamics of microtubules[79].

Oxidative stress and reactive oxygen species (ROS) candamage cell microtubules [80] and inhibit the reshrinkage ofmicrotubules [81]. ROS is known to be a suitable agent thatinterferes with the dynamics of microtubules [82]. In par-ticular, the structure of the α-β tubulin heterodimer issusceptible to oxidation by ROS due to a hefty number ofCys-amino acids [83]. .e physiological level of ROS fa-cilitates the natural polymerisation of tubulin. In contrast,the high level of ROS can inhibit the dynamics and ar-rangement of tubulin through the oxidation of thiol groups[84]. Studies have shown that noscapine NPN derivativescan increase ROS levels in cells. Tubulin regulates

mitochondrial membrane potential by interacting withmitochondrial ducts [85]. .erefore, it causes mitochondrialdysfunction, which causes more ROS production. As a re-sult, mitochondrial function is impaired [86]. Also, nosca-pine can prevent the release of inflammatory mediators byaffecting the tubules and reducing the dynamics of micro-tubules [14].

Various studies have shown that noscapine at maximumconcentrations (100 μM) does not affect the polymerisationof microtubules while keeping the microtubules stationaryfor a longer time, which stops mitosis [14, 87]. Nevertheless,it causes cellular ageing, which develops the further processof cell death, such as autophagy or apoptosis.

4.5. Effects of Noscapine on Sigma Receptors. Sigma ligandsperform awide range of actions, including protecting neuronsagainst oxidative stress and treating cerebral ischemia invarious cell lines, such as retinal ganglion cells [88]. In ad-dition, sigma receptors affect the function of glutamate re-ceptors during nerve damage and inhibit nerve celldestruction [89]. However, this protectivemechanism effect isyet apparent, and studies have shown that glutamate is acritical neurotransmitter in the process of ischemic injury.Excessive increase in glutamate through NMDA receptoractivation leads to increased Ca2+ accumulation within thecell, finally leading to cell damage and cell death, thus playingan essential role in stroke progression. Although blockingNMDA receptors reduces nerve damage, it also inhibits manyof its positive effects. .erefore, we must modulate thefunction of NMDA receptors to control nerve damage [90].

4.5.1. Ischemic Condition. Noscapine exerts its effects byacting on sigma receptors, previously classified as opioidreceptors, that can be used as therapeutic targets to reducecell damages [91]. In the mice model, Kamei et al. [92]showed that noscapine dose-dependently acts as a sigmareceptor agonist. .ese data suggest that noscapine has aprotective role in ischemic conditions [92]. Lack of oxygenor glucose is a significant cause of ischemic brain damage..erefore, activating sigma-1 receptors by noscapine mayprovide neuroprotective effects against hypoxia or glucose-induced cell damage [93]. .e concentration of glutamateand aspartate are increased in these conditions. .us,NMDA receptors are stimulated, and subsequently, theintracellular Ca2+ ion concentration changes. Excessive Ca2+

Table 1: Evaluation of the effect of noscapine on cancer cells along with other first-line drugs.

Noscapine Anticancer drug Type of cancer Growth inhibition (%) In vivo or in vitro Ref.

150–550mg/kg/day Doxorubicin(1.5mg/kg)

Triple negative breastcancer (TNBC)

39.4%–82.9% synergistic interactionbetween noscapine and doxorubicin

In vitro MDA-mb-231 and MDA-mb-

468 cells[36]

300mg/kg/day Gemcitabine(30mg/kg)

Non-small-cell lungcancer (NSCLC)

82.9± 4.5 synergistic interaction betweennoscapine and gemcitabine

In vitro H460tumors [32]

225mg/kg twice perday TMZ (5mg/kg)

Glioblastomamultiforme TMZ-

resistant

Noscapine increased survival in theorthotopic in vivo xenograft model of

TMZ-resistant glioma.

In vitro U251 andA172 cells [30]

100mg/kg/day Docetaxel(0.4 μM)

Triple negative breastcancer

30% increase in number of late apoptoticcells, synergistic interaction

In vitro MDA-mb-231 cells [50]

6 Evidence-Based Complementary and Alternative Medicine

increased within neurons, and endothelial cells can activateCa2+-dependent enzyme cascades that activate various NOisoforms. .erefore, after oxygen or glucose deficiency ornerve damage, the NO level inside the cell increases(Figure 1) [94].

Proteolysis and production of reactive oxygen speciescause cell death [95]. An essential mechanism of sigma-1ligands is the modulation of intracellular calcium homeo-stasis and inhibition of ion channel function, thereby pre-venting damage caused by stimulation of glutamatereceptors [96, 97]..ey protect and reduce intracellular Ca2+concentration [96, 97]. It has been shown that the intra-cellular level of Ca2+ is significantly increased in conditionsof hypoxia or glucose deficiency or damages [93, 98].However, treatment with noscapine 2 μM prevents intra-cellular Ca2+ levels under hypoxia or glucose-deficientconditions [93, 98]. In fact, it has been shown that theprotections were made by sigma-1 receptors, which blocksthe receptors by BD-1047, a selective sigma-1 receptorantagonist; the protection will be hidden [93]. In this regard,Mueller et al. [99] showed that sigma-1 receptors exertneuroprotective effects on retinal ganglion cells by inhibitingCa2+ signalling via VGCC type L [99].

Schulz et al. [100] showed that noscapine treatmentdecreased NO levels in H9C2 cells. In contrast, in the un-treated group, NO levels in H9C2 cells increased signifi-cantly in response to OGD/R. It suggests that noscapine is acardiac protective agent against NO damage. .e results ofthis study showed that BD1047 increases NO levels in H9C2cells, and noscapine significantly inhibits NO accumulationdose-dependently (4 μM) [101]. Noscapine exerts its pro-tective effect on the heart by binding to and activating thesigma-1 receptors, preventing necrosis and apoptosis incardiomyocytes [100].

4.6. Effects of Noscapine on P-Glycoprotein (P-gp).P-glycoproteins (P-gp) are the part of the membrane thatbinds to ATP. It is a transport protein and an active mediatorthat removes harmful substances to the cell (xenobiotic)from the cell. P-gp is overexpressed in cancer cells andreduces their sensitivity to various substances. One of thederivatives of P-gps is efflux mediators, which are still un-known [102]. .e efficiency of this membrane transmitterrequires a significant difference between the tendency toconnect to the substrate site between the two media. Also,structural transitions are from very close junctions to thedisintegration stages of an ATP hydrolytic process in thenucleotide-binding domain. In general, substrates fortranslocation tend to stimulate ATPase activity of P-gp,creating a solid bond between the binding site and thenucleotide-binding domains (NBDs) [103].

On the other hand, a group of compounds such astariquidar have been shown to inhibit P-gp by inhibitingATP hydrolysis [104]. Depending on its effect on ATPase, acompound can stimulate ATPase and act as a substrate, or itcan act as an ATPase inhibitor and act as a P-gp inhibitor.Whether a compound has ATPase-stimulating or inhibitoryactivity depends on the conformation transition [105].

Noscapine has a modulating effect on efflux to be ef-fective on resistant cancer cells by acting on P-gps.Noscapine modulates the activity of this protein by directbinding to P-gp [102]. Noscapine inhibits the proliferationand growth of cancer cells by reducing the substrate for P-gptransport. Noscapine and its derivatives are not substratesfor P-gp but act as an inhibitor of this protein. .e accu-mulation sites of P-gp-transported substrates are reduced bynoscapine derivatives [106]. Noscapine affects resistant andsensitive cell lines, indicating that noscapine does not in-terfere much with P-gp [102].

Noscapine derivatives inhibit calcein-AM transport byP-gp in all cells. .erefore, compounds that alter ATPaseactivity can directly modify and inhibit P-gp function. .eP-gp transfer mechanism requires the transfer of multiplestructures and the interference of two different sites [107]. Inparticular, the displacement of the substrate involves thetransfer from the connecting axis with a high inclination onthe inside to a part with a slight tendency towards the outsideof the cell. It is the active transfer that does this by con-suming ATP [108].

Furthermore, it has been demonstrated that noscapinederivatives appear to affect P-gp expression in cells [109].Also, the 9-nitro-noscapine derivative has been shown toinduce apoptosis and stop mitosis in the ovaries and T-cells,which express P-gp, and are resistant to drugs such aspaclitaxel and vinblastine [48]. Studies have shown thatnoscapine inhibits P-gp function through direct interactionwith the P-gp transmitter [102].

4.7. Effects of Noscapine on VEGF. Angiogenesis is a vitalphenomenon for the survival and development of solidtumours. In the absence of angiogenesis stimuli, tumoursremain silent.

.e essential precursors to angiogenesis in the body arevascular endothelial growth factor (VEGF), basal fibroblastgrowth factor (bFGF), and matrix metalloproteinase(MMP), and cyclooxygenase-2 (COX-2). .erefore, inhib-iting angiogenesis requires antiangiogenesis factors or drugsthat reduce the production of angiogenesis precursors, in-hibit their function, or even prevent angiogenesis precursorsfrom binding to their receptors.

Approximately 60% of malignant tumours have highconcentrations of VEGF, so inhibiting the VEGF pathway isa way to control the rate of tumour growth. For example,treating patients with colon cancer with bevacizumab (amonoclonal antibody against VEGF) has improved patientsurvival [110, 111].

Tubulin-binding agents, such as taxanes, have beenshown to have antiangiogenic effects [112].

Taxanes interfere with endothelial cell proliferation,migration, and differentiation into tiny capillaries to supplytumour food [113, 114]. As a result, taxanes have severe sideeffects, such as peripheral neuropathy, myelosuppression,alopecia, gastrointestinal toxicity, immune suppression, andcardiac toxicity [14, 115]. Recent studies show that nosca-pine has a similar anticancer activity to taxanes [29].Noscapine downregulated hypoxia-mediated expression of

Evidence-Based Complementary and Alternative Medicine 7

HIF-1a in human glioma cells while reducing the potentcytokine secretion of VEGF. Also, high concentrations ofnoscapine inhibit tubule formation by human umbilical veinendothelial cells (HUVECS) [29].

Studies have shown that all noscapine derivativesshowed dose-dependent antiangiogenic activity after 72hours of treatment than those that did not receive noscapine[116]. According to the National Cancer Institute (NCI), IC50> 20, 6.9 µM for Br-noscapine, and 6.79 µM for folate-noscapine can inhibit VEGF (Table 2) [117]. In addition,studies have shown that all noscapine derivatives signifi-cantly prevent the formation of new blood vessels in en-dothelial cells [118].

It has been indicated in an in vivo study that a com-bination of noscapine and concomitant radiation therapyshowed less cell proliferation, more apoptosis, and lessangiogenesis and the formation of tubules in 2H11 endo-thelial cells compared with radiation therapy alone [29]..us, noscapine has anti-inflammatory, antiangiogenesis,and antimetastatic effects. In addition, examination ofhypoxia conditions in human glioma cells has shown thatnoscapine has an inhibitory effect on VEGF, inhibits an-giogenesis, and inhibits TNF-α and NF-κB [116].

4.8. Effects of Noscapine on Apoptosis. Cell death occurs intwo ways, including necrosis and apoptosis. Apoptosis, de-fined as programmed cell death, is an essential process thatoccurs during evolution, homeostasis, and disease. In addi-tion, apoptosis plays a critical role in removing infected,damaged, or other unwanted cells from the body. Unlikenecrosis or other cell death forms that arise from cell rupture,

apoptosis is the silent immunological form of cell death thatcauses cells to rapidly phagocytosis and die without initiatingan inflammatory process. Defects in apoptosis can play a rolein developing diseases such as cancer, so one of the pathwaysstudied in cancer is the path of apoptosis [119].

Apoptosis occurs due to the activation of caspase(cysteine-aspartic proteases) group enzymes. .e intracel-lular ratio of apoptotic-inducing proteins (Bax) to anti-apoptotic proteins (Bcl-2) determines the cell’s susceptibilityto apoptosis. Proapoptotic proteins (Bax) move from thecytoplasm to the mitochondrial wall, causing permeability ofthe outer mitochondrial wall, which leads to the release ofcytochrome C and the onset of apoptosis [120].

Bax can create ion channels and holes in the membraneby modifying the mitochondrial membrane, releasing cy-tochrome C and apoptotic inducing factor (AIF) [121]. Bcl-2is an inhibitor of apoptosis and affects the overall cascade ofapoptosis by binding to Bax and BH3-only proteins like Bim.Phosphorylation of Bcl-2 by apoptosis signal-regulatingkinase-1 reduces its binding to Bax and Bim, and thus itsantiapoptotic activity is lost. .e Bcl-2 family includes Bcl-2and Bcl-X, which can inhibit apoptosis. Various studies haveshown that these proteins inhibit apoptosis by inhibiting therelease of caspases from mitochondria [122].

In a further study, Heidari et al. [123] represented thatnoscapine increased Bax/Bcl-2 expression ratio and inducedapoptosis in both myeloid cell lines, apoptosis-resistantHL60 cells, and apoptosis-resistant K562 cells. However, themolecular mechanism of the anticancer effects of noscapineis unknown. In these noscapine-treated cells, caspases 2, 3, 6,8, and 9 and poly(ADP ribose) polymerase activity increase,and the detection of phosphatidylserine in the outer layer of

Noscapine

Bradykinin B2Receptor

Cough

Angiogenesis

Inflammation

Cancer

Angiogenesis

Inflammation

Cough

Excitotoxicity

Inflammation

Cancer

MitosisMetastasis

Inflammation

Cancer

Metastasis

Inflammation

Angiogenesis

Angiogenesis

Cancer

Cancerresistance

ActivateInhibit

P-gp EGFR& VEGF

& HIF-1α

NF-κB α and β sites oftubulin

Sigma-1Receptor

IschemicReperfusion

Injuries-CNS

-Kidney

IschemicReperfusion

Injuries-CNS

-Kidney

Figure 1: .e possible signalling pathways modulated by noscapine.

8 Evidence-Based Complementary and Alternative Medicine

the cell membrane, chromatin nucleus, and fragmentationDNA induces apoptosis. Furthermore, noscapine increasesBax/Bcl-2 ratio by reducing Bcl-2 expression with Bcl-2phosphorylation (Figure 2). In addition, this study showedthat noscapine can induce apoptosis in leukemic cells re-sistant to apoptosis and could be a new candidate in treatingblood malignancies (Table 2) [123].

Furthermore, in lung cancer cells, apoptosis is activatedby the mitochondrial pathway after treatment with nosca-pine alone and in combination with cisplatin. .is phe-nomenon is attributed to proapoptotic protein upregulationand antiapoptotic downregulation (Bcl-2) [124].

Newcomb et al. showed that noscapine(IC50� 85–131 µM) is a potent inhibitor of proliferation and

induces apoptosis in human glioma. Stimulation of apo-ptosis is associated with activation of C-jun N terminalkinase (JNK) signalling, inhibition of extracellular regulatedkinase (ERK) signalling, and phosphorylation of BCI-2antiapoptotic protein. Noscapine induces apoptosis by se-creting mitochondrial proteins, apoptosis-inducing factor(AIF), or cytochrome C. However, in some glioma cell lines,AIF release has been observed without cytochrome-C release(Figure 2). In fact, it suggests that noscapine induces apo-ptosis by AIF [87].

P53 is a tumour suppressor gene that is the most commoncause of genetic alterations in human tumours. .e productof this gene is a nuclear protein that is involved in cell cyclecontrol, apoptosis, and deletion of gene stability. .us, the

Table 2: Anti-inflammatory effect, the antiapoptotic effects of noscapine.

EffectsTypeof

studyModel Cancer type Dose/Conc Mechanism Years Ref

Inducing apoptosis In vivoBlocking CDH17

gene in colon cancerSW480 cells

Colon cancercells 10 µmol/L ↑Bax, ↓Bcl-2 and ↓Bcl-xL 2017 [135]

Antiproliferation

Invitroand invivo

Triple negativebreast cancer 100mg/kg Increase sensitivity to

docetaxel 2017 [136]

Inducing apoptosis In vivo MCF7 cells Breast cancer Progression in G2/Mtransition 2021 [137]

Inducing apoptosis Invitro

.e expression ofapoptotic genessignificantlyincreased

Endometriosis 3 μg/mL Inhibiting angiogenesisand nitric oxide 2019 [138]

Antineuroinflammation In vivo Parkinson’s disease 10mg/kgEnhancing the expressionof mTOR and prevented

apoptosis2021 [139]

Inducing apoptosis

Invitroand invivo

Human breast cancercell lines MDA-MB-231 and MDA-MB-

468

Breast cancer 50mg/kg

Promoting effect onapoptosis-induced

apoptosis in colon cancercells via p53-dependentpathway reduces VEGF

expression

2019 [140]

Anticancer In vivoLNCaP and PC-3human prostatecancer cell lines

Humanprostate cancer

cell lines50 μM ↓Bcl-2-↑Bax, and ↑Bax/

Bcl-2 ratio 2017 [141]

Inducing apoptosis-tubulins In vivo MCF-7 and MDA-

mb-231 Breast cancer 1.35± 0.2 μM ↑ROS ↓tubulin assembly 2020 [142]

Tubulin In situ STD-NMR 0.6 μM ↓tubulin assembly 2020 [143]

Inhibition of p-glycoprotein In vivo

Human breastadenocarcinoma cell

line MCF7Breast cancer 45.4± 6.5 μM ↓P-gp function 2019 [102]

Inducing apoptosis In vivo.e human coloncancer cell linesHT29 and LoVo

Colon cancercells 75 μM ↓PI3K/mTOR signalling-

↓Warburg effect 2020 [56]

Inducing apoptosis In vivo U87 cellsHuman

glioblastomacells

46.8 µM ↑apoptosis 2019 [144]

Antiangiogenic In vivo Human umbilicalvein endothelial cells

Endothelialcells

11.87 μM for Cl-noscapine, 6.9 μMfor Br-noscapine,and 6.79 μM forfolate-noscapine

Antiangiogenesis activity 2018 [116]

∗STD-NMR: Saturation transfer difference (STD) Nuclear Magnetic Resonance (NMR).

Evidence-Based Complementary and Alternative Medicine 9

function of the P53 protein usually is to regulate cell divi-sion—cell suicide, cell ageing, vascularisation, cell differen-tiation, and DNA metabolism. More than 26,000 geneticmutations have been reported for the p53 gene. .e p53protein is activated by N-terminus phosphorylation by theMAPK protein pathway and the ATM protein pathway.When p53 is phosphorylated, it loses its adhesion to MDM2.As a result, MDM2 protein binds to p53, blocks its action, andtransfers it to the cell cytoplasm..us, P53 anticancer activitycan be done in three ways: (1) P53 protein stimulates DNArepair proteins to address damage to genes. (2) P53 proteinstimulates programmed death (when damaged cells arenonregenerating). (3) P53 protein maintains cell division inthe SG1 phase to provide an opportunity for repair [125, 126].

Aneja and colleagues, in a study, claimed that noscapine,through the p53-dependent pathway, could inhibit cellgrowth and induce apoptosis in HCT116 colon cancer cells[49]. Because P53 is a significant regulator of apoptosis,expression of this factor in response to environmental stressby inhibiting microtubule dynamics can cause apoptosis innoscapine-treated cells. Noscapine leads to the accumulationof p53 within the cell, which in turn causes further secretionof p53. .us, noscapine is p53-dependent and can induceapoptosis in cells by P21 [49].

4.9. Effects of Noscapine on EpidermalGrowth Factor Receptor(EGFR). Various studies have shown that by increasing geneexpression and activating epidermal growth factor receptor(EGFR), many cellular processes such as cell proliferation,differentiation, migration, adhesion, protection against ap-optosis, and angiogenesis are initiated, and the survival ofbreast cancer patients is reduced [127]. .e structure ofEGFR is tyrosine in nature and is involved in the activationof various pathways of AKT/PI3K (phosphoinositol tri-ki-nase) and RAF/RAS and MAPK. In addition, the EGFR-binding ligand activates the AKT/MAPK/STAT and PI3K/RAF/RAS signalling pathways, which together lead toproliferation, adhesion, and cell migration [128].

EGFR is a member of the ErbB family whose proteinkinase activity is involved in the oncogenesis of severalhuman cancers and is recognised as a therapeutic cancertarget. EGFR on TYR 1068 also increases cyclin D1 ex-pression and causes cell proliferation [53]. Noscapine hasbeen shown to selectively inhibit EGFR phosphorylation onresidual Tyr 1068, whose inhibition affects growth and at-tacks other cells [129]. In addition, EGFR aberrations affectvarious cellular signalling pathways in cancer cells, partic-ularly PI3K/AKT and JAK/STAT [130].

Overexpression of EGFR is necessary to enhance mo-tility and cell attack. In vitro data indicate that EGFR andAKT signalling play an essential role in the pathogenesis ofosteosarcoma [131]. In one study, it has been representedthat noscapine inhibited the migration and proliferation ofMG63 osteosarcoma cancer cells in a concentration-de-pendent manner [53]. Moreover, it has been demonstratedthat EGFR phosphorylation (Tyr 1068) decreased with in-creasing noscapine concentration, indicating that noscapinesuppresses EGFR phosphorylation and that MG63 prolif-eration and migration are significantly reduced [53]. Fur-thermore, they concluded that noscapine suppresses theEGFR pathway by inhibiting the expression of cyclin D1 andCDK4/6 and prevents cell transfer from phase G1 to phase S,resulting in antiproliferative effects with induction of apo-ptosis on cells MG63 [53].

4.10. Effects of Noscapine on Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (NF-κB). NF-κB is atranscription factor that, by binding directly to DNA, reg-ulates gene expression and the synthesis of various proteinsinvolved in cellular processes such as survival, proliferation,invasion, and angiogenesis. .is transcription factor is oneof the essential regulators of proinflammatory gene ex-pression, transcribing and synthesising cascades of cytokinesand proinflammatory chemokines such as interleukin (IL)-1β, IL-6, and IL-8 and, consequently, causes inflammatoryresponses [132].

Nos

Activation JNK

Inhibition ERK

PhosphorylationBcl-2

BAX

c c

c c

c

Cytochrom c

Initial caspaseSuch caspase 9

Performing Caspas suchcaspase 3

apoptosis

BAX/BCL-2

Figure 2: Noscapine activates apoptosis in cancer cells by activating the C-jun N terminal kinase signalling pathway, inhibiting extracellularregulated kinase (ERK) signalling, and BCL-2 phosphorylation.

10 Evidence-Based Complementary and Alternative Medicine

Altered NF-κB activity is seen in different types ofdiseases, including stroke, severe epileptic seizures, braindamage, Alzheimer’s, Parkinson’s, gastric ulcer, Crohn’s,Huntington’s, and immune diseases such as psoriasis andcancers. Additionally, improper activation of NF-κB inmany malignancies, including glioblastoma, in which stemcells proliferate, causes tumour cells to invade surroundingtissues and resist radiation therapy [133].

Sung et al. observed that noscapine in human leu-kaemia and myeloma cells inhibited the expression of NF-κB-controlled genes that are essential for the survival,proliferation, and angiogenesis of tumour cells [6]..rough IKβ-kinase, noscapine, inhibits the activity ofNF-κB in malignant cells, leading to inhibition of phos-phorylation and degradation of IKβ-α [6]. Noscapine alsoblocks phosphorylation and nuclear translocation of p65and inhibits NF-κB reporter activity caused by variousanticancer agents NF-κB [6]. In addition, noscapine alsoinhibits NF-κB downstream activity such as the cyclo-oxygenase-2 promoter [6, 134]. Noscapine has beenshown to inhibit NF-κB activity and tumour growth inanimal models of triple-negative breast cancer, along withdoxorubicin [36].

5. Conclusion

Noscapine is a herbal compound that has been usedclinically as an antitussive since the 1950s. In recent years,various pharmacological properties of noscapine havebeen observed in cellular studies, including induction ofapoptosis, decreased microtubule dynamics, inhibition oftumour cell growth, and inhibitory effects on NF-κB,VEGF, and EGFR. In addition, noscapine has anti-in-flammatory effects and significantly reduces the levels ofproinflammatory factors such as IL-1β, IFN-c, IL-6, TNF-α, and antioxidant effects by inhibiting NO and reducingROS levels. Furthermore, noscapine inhibits the growth ofcancer cells and prevents metastasis to other tissues. Inaddition, noscapine easily crosses the blood-brain barrierand exerts appropriate inhibitory effects on glioblastoma,which can be therapeutic. .ese therapeutic effects, alongwith low systemic toxicity, good oral bioavailability, andproper tumour targeting, have made noscapine a viableoption for treating many inflammatory diseases andcancers. Furthermore, noscapine has been shown to havesynergistic effects in cellular studies alongside conven-tional anticancer drugs.

Abbreviations

ACE: Angiotensin-converting enzymeADP ribose: Adenosine diphosphate riboseAIF: Apoptotic inducing factorBBB: Blood-brain barrierBCL-2: Antiapoptotic downregulationbFGF: Basal fibroblast growth factorBK: BradykininCOX-2: Cyclooxygenase-2cGMP: Cyclic guanosine monophosphate

C-JNK: C-jun N terminal kinaseCys: CysteineDOX: DoxorubicinEGFR: Epidermal growth factor receptorERK: Extracellular regulated kinaseFDA: Food and Drug AdministrationGBM: GlioblastomasGSH: GlutathioneGluT1: Glucose transporterGRB2: Growth factor receptor-bound protein 2HIF-1: Hypoxia-inducible factor-1HUVECS: Human umbilical vein endothelial cellsHK2: Hexokinase 2IL-1β: Interleukin 1 betaIL-6: Interleukin-6IL-8: Interleukin-8IFN-c: Interferon-gammaIKK: IKβ-kinaseKKS: Kallikrein-kinin systemLDHB: Lactate dehydrogenase BMAPK: Mitogen-activated protein kinaseMCP1: Monocyte chemoattractant protein 1MMP: Matrix metalloproteinasemg/kg: Milligram/kilogramMGMT: Methylguanine methyltransferaseNADPH: Nicotinamide adenine dinucleotide phosphateNCI: National Cancer InstituteNO: Nitric oxideNPN: N-Propargyl noscapineNMDA: N-Methyl-D-aspartic acidNRFs: Nuclear transcription factorPTEN: Phosphatase and tensin homologPIP3: Phosphoinositide 3PI3K: Phosphoinositol tri-kinaseP-gp: P-glycoproteinPPARs: Peroxisome proliferatorsPKM2: Pyruvate kinase M2ROS: Reactive oxygen speciesTLR: Toll-like receptorTNF-α: Tumor necrosis factor-alfaTNBC: Triple-negative breast cancerVEGF: Vascular endothelial growth factor3-MA: 3-Methyladenine.

Data Availability

No data were used to support this study.

Conflicts of Interest

.e authors declare that they have no conflicts of interestregarding the publication of this paper.

Acknowledgments

.e research reported in this study was supported by anonspecific grant from Mashhad University of MedicalSciences.

Evidence-Based Complementary and Alternative Medicine 11

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16 Evidence-Based Complementary and Alternative Medicine