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Alkaloids Isolated from Natural Herbs as the Anticancer Agents

Alkaloids Isolated from Natural Herbs as the Anticancer Agents Hindawi Publishing Corporation Evidence-Based Complementary and Alternative Medicine Volume 2012, Article ID 485042, 12 pages doi:10.1155/2012/485042 Review Article Jin-Jian Lu, Jiao-Lin Bao, Xiu-Ping Chen, Min Huang, and Yi-Tao Wang State Key Laboratory of Quality Research in Chinese Medicine (University of Macau) and Institute of Chinese Medical Sciences, University of Macau, Avenue Padre Toma’s Pereira, Taipa 999078, Macao, China Correspondence should be addressed to Jin-Jian Lu, jinjianlu@umac.mo andYi-TaoWang, ytwang@umac.mo Received 11 May 2012; Revised 17 July 2012; Accepted 30 July 2012 Academic Editor: Alvin J. Beitz Copyright © 2012 Jin-Jian Lu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Alkaloids are important chemical compounds that serve as a rich reservoir for drug discovery. Several alkaloids isolated from natural herbs exhibit antiproliferation and antimetastasis effects on various types of cancers both in vitro and in vivo. Alkaloids, such as camptothecin and vinblastine, have already been successfully developed into anticancer drugs. This paper focuses on the naturally derived alkaloids with prospective anticancer properties, such as berberine, evodiamine, matrine, piperine, sanguinarine, and tetrandrine, and summarizes the mechanisms of action of these compounds. Based on the information in the literature that is summarized in this paper, the use of alkaloids as anticancer agents is very promising, but more research and clinical trials are necessary before final recommendations on specific alkaloids can be made. 1. Introduction selected for reviewing. Other alkaloids (such as chelery- thrine, chelidonine, fagaronine, lycorine, nitidine chloride, Alkaloids are a highly diverse group of compounds that and solanine) lacking systematic anticancer investigations contain a ring structure and a nitrogen atom. In most have also been mentioned. The aim of this paper is to cases, the nitrogen atom is located inside the heterocyclic summarize and investigate the mechanisms of action of these ring structure [1]. A classification based on biosynthetic compounds to accelerate the discovery of anticancer drugs pathways is mostly used to categorize different alkaloid [1]. derived from alkaloids. We propose that the development Alkaloids have a wide distribution in the plant kingdom and of alkaloids into new anticancer agents has a bright future mainly exist in higher plants, such as those belonging to despitesomedifficulties. Ranunculaceae, Leguminosae, Papaveraceae, Menisperma- ceae, and Loganiaceae [1]. Moreover, several alkaloids exhibit significant biological activities, such as the relieving action of 2. Alkaloids with Anticancer Effects and ephedrine for asthma, the analgesic action of morphine, and the Related Mechanisms the anticancer effects of vinblastine [1–4]. In fact, alkaloids are among the most important active components in natural 2.1. Berberine. Berberine (Figure 1) is an isoquinoline alka- herbs, and some of these compounds have already been loid widely distributed in natural herbs, including Rhizoma successfully developed into chemotherapeutic drugs, such Coptidis, a widely prescribed Chinese herb [6]. It has as camptothecin (CPT), a famous topoisomerase I (TopI) a broad range of bioactivities, such as antiinflammatory, inhibitor [5], and vinblastine, which interacts with tubulin antibacterial, antidiabetes, antiulcer, sedation, protection of [4]. myocardial ischemia-reperfusion injury, expansion of blood Herein, we searched the PubMed database and the vessels, inhibition of platelet aggregation, hepatoprotective, naturally derived alkaloids, such as berberine, evodiamine, and neuroprotective effects [7–11]. Berberine has been used matrine, piperine, sanguinarine, and tetrandrine (Figure 1), in the treatment of diarrhea, neurasthenia, arrhythmia, which have relatively more anticancer studies, have been diabetes, and so forth [11]. Several studies have shown that 2 Evidence-Based Complementary and Alternative Medicine O O N N N N Matrine Berberine Evodiamine Piperine Sanguinarine Tetrandrine Figure 1: The chemical structures of berberine, evodiamine, matrine, piperine, sanguinarine, and tetrandrine. berberine has anticancer potentials by interfering with the [12, 15, 28], and caspases [15, 28]. Furthermore, berberine multiple aspects of tumorigenesis and tumor progression in inhibits the activation of the nuclear factor κ-light-chain- both in vitro and in vivo experiments. These observations enhancer of activated B cells (NF-κB) and induces the have been well summarized in the recent reports [12–14]. formation of intracellular reactive oxygen species (ROS) in Berberine inhibits the proliferation of multiple cancer cell cancer cells [12, 15]. Interestingly, these effects might be lines by inducing cell cycle arrest at the G or G /M phases specific for cancer cells [12]. The effect of berberine on inva- 1 2 and by apoptosis [12, 15, 16]. In addition, berberine induces sion, migration, metastasis, and angiogenesis is mediated endoplasmic reticulum stress [15] and autophagy [17]in through the inhibition of focal adhesion kinase (FAK), NF- cancer cells. However, compared with clinically prescribed κB, urokinase-type plasminogen-activator (u-PA), matrix anticancer drugs, the cytotoxic potency of berberine is much metalloproteinase 2 (MMP-2), and matrix metalloproteinase lower, with an IC generally at 10 μM to 100 μM depending 9 (MMP-9) [20, 29]; reduction of Rho kinase-mediated on the cell type and treatment duration in vitro [12]. Ezrin phosphorylation [19]; reduction of the expression of Besides, berberine also induces morphologic differentiation COX-2, prostaglandin E, and prostaglandin E receptors [30]; in human teratocarcinoma cells [18]. Inhibition of tumor downregulation of hypoxia-inducible factor 1 (HIF-1), vas- invasion and metastasis is an important aspect of berberine’s cular endothelial growth factor (VEGF), proinflammatory anticancer activities [19, 20]. Afew studieshavereported mediators [21, 22], and so forth. berberine’s inhibition of tumor angiogenesis [21, 22]. In addition, its combination with chemotherapeutic drugs 2.2. Evodiamine. Evodiamine (Figure 1), a quinolone alka- or irradiation could enhance the therapeutic effects [23, loid, is one of the major bioactive compounds isolated from 24]. Recently, a study reported that berberine also showed the Chinese herb Evodia rutaecarpa. It possesses antianxiety, promising chemopreventive efficacy in hamster buccal pouch antiobese, antinociceptive, antiinflammatory, antiallergic, carcinogenesis [25]. and anticancer effects. Besides, it has thermoregulation, The potential molecular targets and mechanisms of ber- protection of myocardial ischemia-reperfusion injury and berine are rather complicated. Berberine interacts with DNA vessel-relaxing activities [11, 31–34]. Evodiamine exhibits or RNA to form a berberine-DNA or a berberine-RNA anticancer activities both in vitro and in vivo by inducing complex, respectively [26, 27]. Berberine is also identified as the cell cycle arrest or apoptosis, inhibiting the angiogenesis, an inhibitor of several enzymes, such as N-acetyltransferase invasion, and metastasis in a variety of cancer cell lines (NAT), cyclooxygenase-2 (COX-2), and telomerase [12]. [35–39]. It presents anticancer potentials at micromolar Other mechanisms of berberine are mainly related to its concentrations and even at the nanomolar level in some cell effect on cell cycle arrest and apoptosis, including regulation lines in vitro [40, 41]. Evodiamine also stimulates autophagy, of cyclin-dependent kinase (CDK) family of proteins [12, whichservesasasurvival function [42]. Compared with 28] and expression regulation of B-cell lymphoma 2 (Bcl- other compounds, evodiamine is less toxic to normal human 2) family of proteins (such as Bax, Bcl-2, and Bcl-xL) cells, such as human peripheral blood mononuclear cells Evidence-Based Complementary and Alternative Medicine 3 [37, 43]. It also inhibits the proliferation of adriamycin- or apoptosis, such as E2F-1, Bax, Bcl-2, Fas, and Fas-L resistant human breast cancer NCI/ADR-RES cells both in [59–61, 63, 64, 70]. It inhibits cancer cell invasion par- vitro and in Balb-c/nude mice [44]. Evodiamine (10 mg/kg) tially through inhibition of MMP-2 and MMP-9 expression administrated orally twice daily significantly inhibits the and modulation of the NF-κB signaling pathway [71–73]. tumor growth [44]. Moreover, treatment with 10 mg/kg Matrine has been used in China for cancer therapy. The evodiamine from the 6th day after tumor inoculation into direct inhibition of cancer proliferation by this compound mice reduces lung metastasis and does not affect the body seems not to be the exact mechanism that could explain the weight of mice during the experimental period [35]. reason for its application in cancer treatment. Evodiamine inhibits TopI enzyme, forms the DNA covalent complex with a similar concentration to that of CPT, 2.4. Piperine. Piperine (Figure 1), a piperidine alkaloid iso- and induces DNA damage [45–47]. However, TopI may not lated from Piper nigrum and Piper longum,isacompound be the main target of this compound. Cancer cells treated found in famous spices that have been used for centuries with evodiamine exhibit G /M phase arrest [44, 48, 49] [74]. It exhibits antioxidant, antiinflammatory, antidiarrheal, rather than S phase arrest, which is not consistent with the anticonvulsant, antimutagenic, hypolipidemic, promoting mechanism of classic TopI inhibitors, such as CPT. Therefore, bile secretion, and tumor inhibitory activities [11, 75, 76]. other targets aside from TopI may also be important It is also a known antidepressant of the central nervous for realizing the anticancer potentials of evodiamine. This system [77, 78]. The chemopreventive effects of piperine statement is supported by the fact that evodiamine has effect against several kinds of carcinogen, such as benzo(a)pyrene, on tubulin polymerization [49]. Exposure to evodiamine and 7,12-dimethyl benz(a)anthracene, show its potential as a rapidly increases intracellular ROS followed by an onset of cancer preventive agent [79–85]. Administration of piperine mitochondrial depolarization [50]. The generation of ROS (50 mg/kg or 100 mg/kg per day for 7 days) inhibits solid and nitric oxide acts in synergy and triggers mitochondria- tumor development in mice transplanted with sarcoma 180 dependent apoptosis [42]. Evodiamine also induces caspase- cells [86]. A recent study has shown that piperine inhibits dependent and caspase-independent apoptosis, downregu- breast stem cell self-renewal and does not cause toxicity lates Bcl-2 expression, and upregulates Bax expression in to differentiated cells [87]. It has been demonstrated that some cancer cells [38, 40]. The phosphatidylinositol 3- piperine induced apoptosis and increased the percentage kinase/Akt/caspase and Fas ligand (Fas-L)/NF-κB signaling of cells in G /M phase in 4T1 cells and induced K562 pathways might account for evodiamine-induced cell death. cells to differentiate into macrophages/monocytes [88, 89]. Moreover, these signals could be increased by the ubiquitin- Piperine also has very good antimetastatic properties against proteasome pathway [41]. lung metastasis induced by B16F-10 melanoma cells in mice (200 μM/kg) [90] and suppresses phorbol-12-myristate-13- 2.3. Matrine. Matrine (Figure 1) is a major alkaloid found in acetate (PMA)-induced tumor cell invasion [91]. many Sophora plants, including Sophora flavescens Ait. [51]. Piperine is a potent inhibitor of NF-κB, c-Fos, cAMP It exhibits a wide range of pharmacological properties such response element-binding (CREB), activated transcrip- as antibacterial, antiviral, antiinflammatory, antiasthmatic, tion factor 2 (ATF-2), among others. [92]. It suppresses antiarrhythmic, antiobesity, anticancer, diuretic, choleretic, PMA-induced MMP-9 expression via the inhibition of hepatoprotective, nephroprotective, and cardioprotective PKCα/extracellular signal-regulated kinase (ERK) 1/2 and effects [11, 52–58]. It has been used for treatment of bacillary reduction of NF-κB/AP-1 activation [91]. Remarkably, piper- dysentery, enteritis, malignant pleural effusion, and so forth ine also inhibits the functions of P-glycoprotein (P-gp) and in China [11], and the anticancer effects have also been CYP3A4, which not only affects drug metabolism but also widely studied [59–61]. Although the needed concentration re-sensitizes multidrug resistant (MDR) cancer cells [93, 94]. of matrine to inhibit cancer cell proliferation is relatively high Piperine increases the therapeutic efficacy of docetaxel in a (i.e., at millimolar level) [59, 60], it has no significant effects xenograft model without inducing more adverse effects on on the viability of normal cells [60]. Matrine inhibits the the treated mice by inhibiting CYP3A4, one of the main proliferation of various types of cancer cells mainly through metabolizing enzymes of docetaxel [95]. mediation of G cell cycle arrest or apoptosis [59, 60, 62–64]. Apoptosis and autophagy could be both induced by matrine in human cancer cells, such as hepatoma G2 cells and SGC- 2.5. Sanguinarine. Sanguinarine (Figure 1) is a benzophe- 7901 cells [65, 66]. Matrine also induces the differentiation of nanthridine alkaloid isolated from the Papaveracea family, K562 cells and presents antiangiogenesis activities [67, 68]. which includes Sanguinaria canadensis L. and Chelidonium The in vivo anticancer efficacy of matrine has already been majus L. [96, 97]. It has antibacterial, antifungal, antis- evaluated in H22 cells, MNNG/HOS cells, 4T1 cells and chistosomal, antiplatelet, and antiinflammatory properties BxPC-3 cells in BALB/c mice, among others [60, 61, 68, 69]. [11, 98–100], and is used for schistosomiasis control [11]. For example, matrine at 50 mg/kg or 100 mg/kg inhibits Sanguinarine also exhibits anticancer potentials [101–104] MNNG/HOS xenograft growth [61], and it reduces the and is currently receiving attention from researchers. Data pancreatic tumor volumes compared to those of control at from in vitro studies indicates that this alkaloid presents the similar doses [60]. anticancer effects at concentrations less than ten micromoles However, the exact targets of matrine are still unclear. in most cases. Sanguinarine induces cell cycle arrest at Matrine affects many proteins involved in cell proliferation different phases or apoptosis in a variety of cancer cells 4 Evidence-Based Complementary and Alternative Medicine [101, 102, 104–107]. It remarkably sensitizes breast cancer mice (10 mg/kg/day) have fewer metastases than vehicle- cells to tumor necrosis factor (TNF)-related apoptosis- treated mice, and no acute toxicity or obvious changes can inducing ligand-mediated apoptosis [105]. Sanguinarine be observed in the body weight of both groups [132]. also shows antiangiogenic effects in mice (5 mg/kg), presents Coadministration of tetrandrine restores the sensitivity anti-invasive effects, and overcomes P-gp-mediated MDR of MDR cancer cells to doxorubicin, paclitaxel, docetaxel, phenotype [108–110]. A strategy involving the coadminis- and vincristine [133–135] through the inhibition of P-gp. tration of COX-2 inhibitors and sanguinarine has been rec- In mice with MDR MCF-7/adr or KBv200 cell xenografts, ommended for the management of prostate cancer [111]. It co-administration of tetrandrine increases the anticancer has also been suggested that sanguinarine may be developed activity of doxorubicin and vincristine without a significant as an agent for the management of conditions elicited by increase in toxicity [133, 135]. Hence, tetrandrine holds a ultraviolet exposure such as skin cancer [112]. great promise as a MDR modulator for the treatment of The most possible mechanism responsible for the anti- P-gp-mediated MDR cancers. Tetrandrine appears to be a cancer effects of this compound is its ability to directly promising candidate for combining with several chemother- interact with glutathione (GSH). This interaction severely apeutic agents, such as 5-fluorouracil and cisplatin, in depletes cellular GSH and induces ROS generation [102, 103, vitro or in vivo [126, 136, 137]. It enhances tamoxifen- 105, 113]. Pretreatment of N-acetyl cysteine or catalase pre- induced antiproliferation by inhibiting phosphoinositide- vents the sanguinarine-induced ROS production and cyto- dependent kinase 1 [138]. Tetrandrine also enhances the toxicity [102, 113]. This mechanism is very similar to that of radio sensitivity of various cancer cells mainly by affecting the TopII inhibitor salvicine, a diterpene quinone synthesized the radiation-induced cell cycle arrest and redistributing via the structural modification of a natural compound the cell cycle [139–143]. All these observations are rational isolated from Salvia prionitis lance [114, 115]. Sanguinarine evidence supporting the application of tetrandrine as an is a selective inhibitor of mitogen-activated protein kinase adjunct for cancer chemotherapy or radiotherapy. phosphatase 1 (MKP-1), which is overexpressed in many Activation of glycogen synthase kinase 3β (GSK-3β), tumor cells [116]. The disruption of microtubule assembly generation of ROS, activation of p38 mitogen-activated dynamics [117], the nucleocytoplasmic trafficking of cyclin protein kinase (p38 MAPK), and inhibition of Wnt/beta- D1 and TopII [118], and the induction of DNA damage [109] catenin signaling might contribute to the anticancer effects of also contributes to, at least in part, the anticancer effects tetrandrine [126, 127, 144–146]. Tetrandrine also effectively of this compound. Sanguinarine is a potent suppressor of up-regulates p53, p21, p27, and Fas [123, 124, 145, 147]; NF-κB activation induced by TNF, interleukin-1, phorbol down-regulates Akt phosphorylation, CDKs, and cyclins ester, and okadaic acid, but not that activated by hydrogen [124, 145, 148]; modulates the members of the Bcl-2 family peroxide or ceramide [119]. It also effectively inhibits the including Bax, Bcl-xL, and Bid [147, 148]; activates caspases signal transducer and activator of transcription 3 activation [145, 147]. (STAT-3) [120]; downregulates CDKs, cyclins, MMP-2, and MMP-9 [107, 110]; upregulates p21, p27 [107], and the 2.7. Other Alkaloids with Anticancer Effects. Aside from the phosphorylation of p53 [101]; modulates the members of the aforementioned alkaloids, other alkaloids such as chelery- Bcl-2 family including Bax, Bak, Bid, Bcl-2, and Bcl-xL [101, thrine isolated from Toddalia asiatica (L.) Lam, chelidonine 105, 106]; activates caspases [104–106]; and upregulates isolated from Chelidonium majus L., fagaronine isolated from death receptor 5 (DR-5) [104]. Fagara zanthoxyloides Lam., lycorine isolated from Lycoris, nitidine chloride isolated from Zanthoxylum nitidum (Roxb.) DC., solanine isolated from Solanum tuberosum, sopho- 2.6. Tetrandrine. Tetrandrine (Figure 1), a bisbenzyliso- carpine isolated from Sophora alopecuroides L., trigonelline quinoline alkaloid from the root of Stephania tetrandra, isolated from trigonella foenum-graecum also present anti- exhibits a broad range of pharmacological activities, includ- cancer potentials with diversiform mechanisms [11, 149– ing immunomodulating, antihepatofibrogenetic, antiinflam- 153]. However, reports on the anticancer activities and matory, antiarrhythmic, antiportal hypertension, anticancer underlying mechanism of actions of these compounds are and neuroprotective activities [11, 121]. It generally presents limited. its anticancer effects in the micromolar concentrations. Tetrandrine induces different phases of cell cycle arrest, depends on cancer cell types [122–124], and also induces 3. Discussion apoptosis in many human cancer cells, including leukemia, bladder, colon, hepatoma, and lung [122–130]. In vivo In this paper, we summarized the recent progress of several experiments have also demonstrated the potential value of typical alkaloids with anticancer activities and presented tetrandrine against cancer activity [126, 127, 131]. For exam- some characteristics of these compounds. On the basis of the ple, the survival of mice subcutaneously inoculated with previous studies, alkaloids with anticancer activities reflect CT-26 cells is extended after daily oral gavage of 50 mg/kg diversity at least in three aspects. or 150 mg/kg of tetrandrine [127]. Tetrandrine also inhibits First, the source of alkaloids with anticancer potentials the expression of VEGF in glioma cells, has cytotoxic effect is very extensive. Most of the aforementioned alkaloids are on ECV304 human umbilical vein endothelial cells, and from different families, and the biosynthesis of these com- suppresses in vivo angiogenesis [131]. Tetrandrine-treated pounds is also varied. For example, berberine is isolated from B M P Autophagy Anti-MDR E M P S T B E M P S T Evidence-Based Complementary and Alternative Medicine 5 BE MP S T Antiangiogenesis Anticancer Differentiation BP B: Berberine P: Piperine E: Evodiamine S: Sanguinarine M: Matrine T: Tetrandrine Figure 2: Berberine, evodiamine, matrine, piperine, sanguinarine, and tetrandrine restrain cancer by modulating multiple signaling pathways, resulting in the inhibition of the initiation of carcinogenesis, induction of cell cycle arrest, apoptosis, autophagy, or differentiation, and inhibition of metastasis, angiogenesis, and so forth. Ranunculaceae and roots in phenylalanine and tyrosine, millimole [60]. Therefore, modification of the compound via whereas evodiamine is isolated from Rutaceae and roots in chemical methods may be a good strategy. This observation tryptophan [1]. Second, the pharmacological activities of also indicates that combination therapy probably provides these alkaloids are varied [11, 12, 154]. For instance, piperine an optimal venue for the clinical application of these com- and berberine are used to treat epilepsy and diarrhea, pounds because most of these alkaloids exhibit synergistic or respectively [155, 156], and both of these compounds show enhancement effects when combined with chemotherapeutic anticancer and other pharmacological effects. Third, the drugs in both in vitro and in vivo experiments [95, 136, 157, research focuses of these anticancer alkaloids are also very 158]. different. Research on piperine is usually focused on cancer Second, alkaloids isolated from natural herbs seem to prevention [82, 85], whereas that on most other alkaloids have many targets to realize their multiple pharmacological is mainly focused on cancer chemotherapy, especially on effects (Figure 3), indicating that most of them are “dirty the evaluation of antiproliferative activity [12, 37, 113, 124]. compounds.” These “dirty compounds” are a pressing medi- Figure 2 summarizes the different roles of the aforemen- cal necessity, especially for the treatment of complex diseases tioned six alkaloids to achieve their anticancer effects. such as cancer [159]. However, the discovery of the molecular In addition to their diversity, the anticancer alkaloids also targets and mechanisms of these alkaloids still has a long way have several other characteristics or/and issues which should to go. Recent developments in biology, such as the emergence be addressed. First, the range of alkaloid concentration of the “-omics” fields of study, surface plasmon resonance necessary to elicit the anticancer effects is wide [4, 5, 12, technology, and siRNA, may greatly facilitate researches in 60, 124]. The needed concentration is relatively higher for this area [4, 160–163]. most of the aforementioned alkaloids to produce anticancer Third, most of these alkaloids have poor water solubility effects, compared with the widely used chemotherapeutic and low bioavailability and are hard to reach the specific drugssuchasCPT [5] and vinblastine [4], although both cancer site. In addition to the structural modification, are also naturally derived alkaloids. The concentration of changing the drug delivery system could be another strategy. matrine used to produce anticancer effects even reaches The development of nanotechnology may bring hope to solve B E M Antimetastasis Cell cycle arrest M P S T BE M S T Chemoprevention Apoptosis 6 Evidence-Based Complementary and Alternative Medicine Fas-L Fas-L Piperine Sanguinarine Tetrandrine Berberine Evodiamine Matrine P-gp P-gp DR-5 Fas Cell Piperine Sanguinar S S S S S ine Evodiamine Matrine membr m ane Fas Fas Berberine Tetrandrine NO Akt Cyclin D1 MMP-2 c-Fos GSH p38 MAPK COX-2 ROS PKC MMP-9 CDKs ROS ATF-2 ERK NF-κB NF-κB MMP-9 E2F1 NF-κB STAT3 Cyclin B1 JNK Caspases Caspases MMP-2 p21 Cyclin D1 p27 Wnt CREB Bax p27 Bax CDKs Bax CDKs PKCα p21 Bcl-2 Bcl-2 Caspases Bcl-2 FAK p53 p53 Tubulin MMP-9 GSK3β u-PA cdc25C p27 ERK Cyclin D1 MMP-2 Akt p38 MAPK p21 HIF-1 MKP MKP-1 1 C C Cy y yc c cl l lin D1 in D1 in D1 p27 p27 NA NAT T T Tu ubulin bulin p21 p21 GADD153 GADD153 GADD153 E Ev vo odiamine diamine Ber Berb ber erine-DN ine-DNA A Ber Berb ber eri ine-RN ne-RNA A c co omple mplex x c co omple mplex x Ber Berb be er ri ine ne To Top II p II To Top p I I T T Te el lomer omeras ase e DN DNA damage A damage d Sanguinar Sanguinarine ine N Nuclear membr l ane : Activation or upregulation Inhibition or downregulation Figure 3: The schematic diagram of the molecular machinery and possible targets for the antineoplastic properties of berberine, evodiamine, matrine, piperine, sanguinarine, and tetrandrine. ATF-2: activated transcription factor 2; Bax: Bcl-2-associated X protein; Bcl-2: B-cell lymphoma 2; CDKs: cyclin-dependent kinases; COX-2: cyclooxygenase 2; CREB: cAMP response element-binding; DR-5: death receptor 5; ERK: extracellular signal-regulated kinase; FAK: focal adhesion kinase; Fas-L: Fas ligand; GADD153: growth arrest and DNA-damage- inducible gene 153; GSH: glutathione; GSK3β: glycogen synthase kinase 3β; HIF-1: hypoxia-inducible factor 1; MKP-1: mitogen-activated protein kinase phosphatase 1; MMP-2: matrix metalloproteinase 2; MMP-9: matrix metalloproteinase 9; NAT: N-acetyltransferase; NF-κB: nuclear factor κ-light-chain-enhancer of activated B cells; NOS: nitric oxide synthase; p38 MAPK: p38 mitogen-activated protein kinase; PKC: protein kinase C; P-gp: P-glycoprotein; ROS: reactive oxygen species; STAT-3: signal transducer and activator of transcription 3; TopI: topoisomerase I; TopII: topoisomerase II; u-PA: urokinase-type plasminogen-activator. these problems, and actually, there have been already some berberine for the treatment of diabetes or metabolic syn- successful cases [164, 165]. drome, there is no report about the clinical trial for cancer Fourth, the toxicity of these compounds also cannot prevention or treatment using the aforementioned alkaloids. be ignored. For example, the most common side effects As there is a big jump from experiment researches to clinical of berberine include anaphylaxis, constipation, and skin ones, it is necessary to carry out some clinical anticancer allergies [166]. Berberine can displace bilirubin from serum- trials for these alkaloids, such as berberine and tetrandrine. binding proteins and cause kernicterus, jaundice, and brain In conclusion, for the future work in the field, (1) damage in infants [166–168]. Neurotoxicity, immunotox- the exact anticancer mechanisms of alkaloids should be icity, and reproductive toxicity induced by piperine have further identified using new pharmacological technologies; been reported [169–171], and hepatotoxicity and embryonic (2) the chemical structures of these lead compounds may be toxicity can also be induced by sanguinarine [172, 173]. transformed via pharmaceutical chemistry; (3) the effective Therefore, alkaloids isolated from natural herbs are not combinational therapy methods may be explored; (4) the always safe. The dosages, the routes of administration and effective drug delivery systems need to be developed; (5) the the treatment procedures, among others, are very important. additional clinical anticancer trials for these alkaloids need to The transformation of chemical structures and the applica- be performed. tion of newdrugdeliverysystems mayreducethe toxicities of these compounds. 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Alkaloids Isolated from Natural Herbs as the Anticancer Agents

Evidence-based Complementary and Alternative MedicineJan 1, 2012

Alkaloids Isolated from Natural Herbs as the Anticancer Agents

Abstract

Hindawi Publishing Corporation Evidence-Based Complementary and Alternative Medicine Volume 2012, Article ID 485042, 12 pages doi:10.1155/2012/485042 Review Article Jin-Jian Lu, Jiao-Lin Bao, Xiu-Ping Chen, Min Huang, and Yi-Tao Wang State Key Laboratory of Quality Research in Chinese Medicine (University of Macau) and Institute of Chinese Medical Sciences, University of Macau, Avenue Padre Toma’s Pereira, Taipa 999078, Macao, China Correspondence should be addressed to Jin-Jian Lu, jinjianlu@umac.mo andYi-TaoWang, ytwang@umac.mo Received 11 May 2012; Revised 17 July 2012; Accepted 30 July 2012 Academic Editor: Alvin J. Beitz Copyright © 2012 Jin-Jian Lu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Alkaloids are important chemical compounds that serve as a rich reservoir for drug discovery. Several alkaloids isolated from natural herbs exhibit antiproliferation and antimetastasis effects on various types of cancers both in vitro and in vivo. Alkaloids, such as camptothecin and vinblastine, have already been successfully developed into anticancer drugs. This paper focuses on the naturally derived alkaloids with prospective anticancer properties, such as berberine, evodiamine, matrine, piperine, sanguinarine, and tetrandrine, and summarizes the mechanisms of action

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Abstract

Hindawi Publishing Corporation Evidence-Based Complementary and Alternative Medicine Volume 2012, Article ID 485042, 12 pages doi:10.1155/2012/485042 Review Article Jin-Jian Lu, Jiao-Lin Bao, Xiu-Ping Chen, Min Huang, and Yi-Tao Wang State Key Laboratory of Quality Research in Chinese Medicine (University of Macau) and Institute of Chinese Medical Sciences, University of Macau, Avenue Padre Toma’s Pereira, Taipa 999078, Macao, China Correspondence should be addressed to Jin-Jian Lu, jinjianlu@umac.mo andYi-TaoWang, ytwang@umac.mo Received 11 May 2012; Revised 17 July 2012; Accepted 30 July 2012 Academic Editor: Alvin J. Beitz Copyright © 2012 Jin-Jian Lu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Alkaloids are important chemical compounds that serve as a rich reservoir for drug discovery. Several alkaloids isolated from natural herbs exhibit antiproliferation and antimetastasis effects on various types of cancers both in vitro and in vivo. Alkaloids, such as camptothecin and vinblastine, have already been successfully developed into anticancer drugs. This paper focuses on the naturally derived alkaloids with prospective anticancer properties, such as berberine, evodiamine, matrine, piperine, sanguinarine, and tetrandrine, and summarizes the mechanisms of action of these compounds. Based on the information in the literature that is summarized in this paper, the use of alkaloids as anticancer agents is very promising, but more research and clinical trials are necessary before final recommendations on specific alkaloids can be made. 1. Introduction selected for reviewing. Other alkaloids (such as chelery- thrine, chelidonine, fagaronine, lycorine, nitidine chloride, Alkaloids are a highly diverse group of compounds that and solanine) lacking systematic anticancer investigations contain a ring structure and a nitrogen atom. In most have also been mentioned. The aim of this paper is to cases, the nitrogen atom is located inside the heterocyclic summarize and investigate the mechanisms of action of these ring structure [1]. A classification based on biosynthetic compounds to accelerate the discovery of anticancer drugs pathways is mostly used to categorize different alkaloid [1]. derived from alkaloids. We propose that the development Alkaloids have a wide distribution in the plant kingdom and of alkaloids into new anticancer agents has a bright future mainly exist in higher plants, such as those belonging to despitesomedifficulties. Ranunculaceae, Leguminosae, Papaveraceae, Menisperma- ceae, and Loganiaceae [1]. Moreover, several alkaloids exhibit significant biological activities, such as the relieving action of 2. Alkaloids with Anticancer Effects and ephedrine for asthma, the analgesic action of morphine, and the Related Mechanisms the anticancer effects of vinblastine [1–4]. In fact, alkaloids are among the most important active components in natural 2.1. Berberine. Berberine (Figure 1) is an isoquinoline alka- herbs, and some of these compounds have already been loid widely distributed in natural herbs, including Rhizoma successfully developed into chemotherapeutic drugs, such Coptidis, a widely prescribed Chinese herb [6]. It has as camptothecin (CPT), a famous topoisomerase I (TopI) a broad range of bioactivities, such as antiinflammatory, inhibitor [5], and vinblastine, which interacts with tubulin antibacterial, antidiabetes, antiulcer, sedation, protection of [4]. myocardial ischemia-reperfusion injury, expansion of blood Herein, we searched the PubMed database and the vessels, inhibition of platelet aggregation, hepatoprotective, naturally derived alkaloids, such as berberine, evodiamine, and neuroprotective effects [7–11]. Berberine has been used matrine, piperine, sanguinarine, and tetrandrine (Figure 1), in the treatment of diarrhea, neurasthenia, arrhythmia, which have relatively more anticancer studies, have been diabetes, and so forth [11]. Several studies have shown that 2 Evidence-Based Complementary and Alternative Medicine O O N N N N Matrine Berberine Evodiamine Piperine Sanguinarine Tetrandrine Figure 1: The chemical structures of berberine, evodiamine, matrine, piperine, sanguinarine, and tetrandrine. berberine has anticancer potentials by interfering with the [12, 15, 28], and caspases [15, 28]. Furthermore, berberine multiple aspects of tumorigenesis and tumor progression in inhibits the activation of the nuclear factor κ-light-chain- both in vitro and in vivo experiments. These observations enhancer of activated B cells (NF-κB) and induces the have been well summarized in the recent reports [12–14]. formation of intracellular reactive oxygen species (ROS) in Berberine inhibits the proliferation of multiple cancer cell cancer cells [12, 15]. Interestingly, these effects might be lines by inducing cell cycle arrest at the G or G /M phases specific for cancer cells [12]. The effect of berberine on inva- 1 2 and by apoptosis [12, 15, 16]. In addition, berberine induces sion, migration, metastasis, and angiogenesis is mediated endoplasmic reticulum stress [15] and autophagy [17]in through the inhibition of focal adhesion kinase (FAK), NF- cancer cells. However, compared with clinically prescribed κB, urokinase-type plasminogen-activator (u-PA), matrix anticancer drugs, the cytotoxic potency of berberine is much metalloproteinase 2 (MMP-2), and matrix metalloproteinase lower, with an IC generally at 10 μM to 100 μM depending 9 (MMP-9) [20, 29]; reduction of Rho kinase-mediated on the cell type and treatment duration in vitro [12]. Ezrin phosphorylation [19]; reduction of the expression of Besides, berberine also induces morphologic differentiation COX-2, prostaglandin E, and prostaglandin E receptors [30]; in human teratocarcinoma cells [18]. Inhibition of tumor downregulation of hypoxia-inducible factor 1 (HIF-1), vas- invasion and metastasis is an important aspect of berberine’s cular endothelial growth factor (VEGF), proinflammatory anticancer activities [19, 20]. Afew studieshavereported mediators [21, 22], and so forth. berberine’s inhibition of tumor angiogenesis [21, 22]. In addition, its combination with chemotherapeutic drugs 2.2. Evodiamine. Evodiamine (Figure 1), a quinolone alka- or irradiation could enhance the therapeutic effects [23, loid, is one of the major bioactive compounds isolated from 24]. Recently, a study reported that berberine also showed the Chinese herb Evodia rutaecarpa. It possesses antianxiety, promising chemopreventive efficacy in hamster buccal pouch antiobese, antinociceptive, antiinflammatory, antiallergic, carcinogenesis [25]. and anticancer effects. Besides, it has thermoregulation, The potential molecular targets and mechanisms of ber- protection of myocardial ischemia-reperfusion injury and berine are rather complicated. Berberine interacts with DNA vessel-relaxing activities [11, 31–34]. Evodiamine exhibits or RNA to form a berberine-DNA or a berberine-RNA anticancer activities both in vitro and in vivo by inducing complex, respectively [26, 27]. Berberine is also identified as the cell cycle arrest or apoptosis, inhibiting the angiogenesis, an inhibitor of several enzymes, such as N-acetyltransferase invasion, and metastasis in a variety of cancer cell lines (NAT), cyclooxygenase-2 (COX-2), and telomerase [12]. [35–39]. It presents anticancer potentials at micromolar Other mechanisms of berberine are mainly related to its concentrations and even at the nanomolar level in some cell effect on cell cycle arrest and apoptosis, including regulation lines in vitro [40, 41]. Evodiamine also stimulates autophagy, of cyclin-dependent kinase (CDK) family of proteins [12, whichservesasasurvival function [42]. Compared with 28] and expression regulation of B-cell lymphoma 2 (Bcl- other compounds, evodiamine is less toxic to normal human 2) family of proteins (such as Bax, Bcl-2, and Bcl-xL) cells, such as human peripheral blood mononuclear cells Evidence-Based Complementary and Alternative Medicine 3 [37, 43]. It also inhibits the proliferation of adriamycin- or apoptosis, such as E2F-1, Bax, Bcl-2, Fas, and Fas-L resistant human breast cancer NCI/ADR-RES cells both in [59–61, 63, 64, 70]. It inhibits cancer cell invasion par- vitro and in Balb-c/nude mice [44]. Evodiamine (10 mg/kg) tially through inhibition of MMP-2 and MMP-9 expression administrated orally twice daily significantly inhibits the and modulation of the NF-κB signaling pathway [71–73]. tumor growth [44]. Moreover, treatment with 10 mg/kg Matrine has been used in China for cancer therapy. The evodiamine from the 6th day after tumor inoculation into direct inhibition of cancer proliferation by this compound mice reduces lung metastasis and does not affect the body seems not to be the exact mechanism that could explain the weight of mice during the experimental period [35]. reason for its application in cancer treatment. Evodiamine inhibits TopI enzyme, forms the DNA covalent complex with a similar concentration to that of CPT, 2.4. Piperine. Piperine (Figure 1), a piperidine alkaloid iso- and induces DNA damage [45–47]. However, TopI may not lated from Piper nigrum and Piper longum,isacompound be the main target of this compound. Cancer cells treated found in famous spices that have been used for centuries with evodiamine exhibit G /M phase arrest [44, 48, 49] [74]. It exhibits antioxidant, antiinflammatory, antidiarrheal, rather than S phase arrest, which is not consistent with the anticonvulsant, antimutagenic, hypolipidemic, promoting mechanism of classic TopI inhibitors, such as CPT. Therefore, bile secretion, and tumor inhibitory activities [11, 75, 76]. other targets aside from TopI may also be important It is also a known antidepressant of the central nervous for realizing the anticancer potentials of evodiamine. This system [77, 78]. The chemopreventive effects of piperine statement is supported by the fact that evodiamine has effect against several kinds of carcinogen, such as benzo(a)pyrene, on tubulin polymerization [49]. Exposure to evodiamine and 7,12-dimethyl benz(a)anthracene, show its potential as a rapidly increases intracellular ROS followed by an onset of cancer preventive agent [79–85]. Administration of piperine mitochondrial depolarization [50]. The generation of ROS (50 mg/kg or 100 mg/kg per day for 7 days) inhibits solid and nitric oxide acts in synergy and triggers mitochondria- tumor development in mice transplanted with sarcoma 180 dependent apoptosis [42]. Evodiamine also induces caspase- cells [86]. A recent study has shown that piperine inhibits dependent and caspase-independent apoptosis, downregu- breast stem cell self-renewal and does not cause toxicity lates Bcl-2 expression, and upregulates Bax expression in to differentiated cells [87]. It has been demonstrated that some cancer cells [38, 40]. The phosphatidylinositol 3- piperine induced apoptosis and increased the percentage kinase/Akt/caspase and Fas ligand (Fas-L)/NF-κB signaling of cells in G /M phase in 4T1 cells and induced K562 pathways might account for evodiamine-induced cell death. cells to differentiate into macrophages/monocytes [88, 89]. Moreover, these signals could be increased by the ubiquitin- Piperine also has very good antimetastatic properties against proteasome pathway [41]. lung metastasis induced by B16F-10 melanoma cells in mice (200 μM/kg) [90] and suppresses phorbol-12-myristate-13- 2.3. Matrine. Matrine (Figure 1) is a major alkaloid found in acetate (PMA)-induced tumor cell invasion [91]. many Sophora plants, including Sophora flavescens Ait. [51]. Piperine is a potent inhibitor of NF-κB, c-Fos, cAMP It exhibits a wide range of pharmacological properties such response element-binding (CREB), activated transcrip- as antibacterial, antiviral, antiinflammatory, antiasthmatic, tion factor 2 (ATF-2), among others. [92]. It suppresses antiarrhythmic, antiobesity, anticancer, diuretic, choleretic, PMA-induced MMP-9 expression via the inhibition of hepatoprotective, nephroprotective, and cardioprotective PKCα/extracellular signal-regulated kinase (ERK) 1/2 and effects [11, 52–58]. It has been used for treatment of bacillary reduction of NF-κB/AP-1 activation [91]. Remarkably, piper- dysentery, enteritis, malignant pleural effusion, and so forth ine also inhibits the functions of P-glycoprotein (P-gp) and in China [11], and the anticancer effects have also been CYP3A4, which not only affects drug metabolism but also widely studied [59–61]. Although the needed concentration re-sensitizes multidrug resistant (MDR) cancer cells [93, 94]. of matrine to inhibit cancer cell proliferation is relatively high Piperine increases the therapeutic efficacy of docetaxel in a (i.e., at millimolar level) [59, 60], it has no significant effects xenograft model without inducing more adverse effects on on the viability of normal cells [60]. Matrine inhibits the the treated mice by inhibiting CYP3A4, one of the main proliferation of various types of cancer cells mainly through metabolizing enzymes of docetaxel [95]. mediation of G cell cycle arrest or apoptosis [59, 60, 62–64]. Apoptosis and autophagy could be both induced by matrine in human cancer cells, such as hepatoma G2 cells and SGC- 2.5. Sanguinarine. Sanguinarine (Figure 1) is a benzophe- 7901 cells [65, 66]. Matrine also induces the differentiation of nanthridine alkaloid isolated from the Papaveracea family, K562 cells and presents antiangiogenesis activities [67, 68]. which includes Sanguinaria canadensis L. and Chelidonium The in vivo anticancer efficacy of matrine has already been majus L. [96, 97]. It has antibacterial, antifungal, antis- evaluated in H22 cells, MNNG/HOS cells, 4T1 cells and chistosomal, antiplatelet, and antiinflammatory properties BxPC-3 cells in BALB/c mice, among others [60, 61, 68, 69]. [11, 98–100], and is used for schistosomiasis control [11]. For example, matrine at 50 mg/kg or 100 mg/kg inhibits Sanguinarine also exhibits anticancer potentials [101–104] MNNG/HOS xenograft growth [61], and it reduces the and is currently receiving attention from researchers. Data pancreatic tumor volumes compared to those of control at from in vitro studies indicates that this alkaloid presents the similar doses [60]. anticancer effects at concentrations less than ten micromoles However, the exact targets of matrine are still unclear. in most cases. Sanguinarine induces cell cycle arrest at Matrine affects many proteins involved in cell proliferation different phases or apoptosis in a variety of cancer cells 4 Evidence-Based Complementary and Alternative Medicine [101, 102, 104–107]. It remarkably sensitizes breast cancer mice (10 mg/kg/day) have fewer metastases than vehicle- cells to tumor necrosis factor (TNF)-related apoptosis- treated mice, and no acute toxicity or obvious changes can inducing ligand-mediated apoptosis [105]. Sanguinarine be observed in the body weight of both groups [132]. also shows antiangiogenic effects in mice (5 mg/kg), presents Coadministration of tetrandrine restores the sensitivity anti-invasive effects, and overcomes P-gp-mediated MDR of MDR cancer cells to doxorubicin, paclitaxel, docetaxel, phenotype [108–110]. A strategy involving the coadminis- and vincristine [133–135] through the inhibition of P-gp. tration of COX-2 inhibitors and sanguinarine has been rec- In mice with MDR MCF-7/adr or KBv200 cell xenografts, ommended for the management of prostate cancer [111]. It co-administration of tetrandrine increases the anticancer has also been suggested that sanguinarine may be developed activity of doxorubicin and vincristine without a significant as an agent for the management of conditions elicited by increase in toxicity [133, 135]. Hence, tetrandrine holds a ultraviolet exposure such as skin cancer [112]. great promise as a MDR modulator for the treatment of The most possible mechanism responsible for the anti- P-gp-mediated MDR cancers. Tetrandrine appears to be a cancer effects of this compound is its ability to directly promising candidate for combining with several chemother- interact with glutathione (GSH). This interaction severely apeutic agents, such as 5-fluorouracil and cisplatin, in depletes cellular GSH and induces ROS generation [102, 103, vitro or in vivo [126, 136, 137]. It enhances tamoxifen- 105, 113]. Pretreatment of N-acetyl cysteine or catalase pre- induced antiproliferation by inhibiting phosphoinositide- vents the sanguinarine-induced ROS production and cyto- dependent kinase 1 [138]. Tetrandrine also enhances the toxicity [102, 113]. This mechanism is very similar to that of radio sensitivity of various cancer cells mainly by affecting the TopII inhibitor salvicine, a diterpene quinone synthesized the radiation-induced cell cycle arrest and redistributing via the structural modification of a natural compound the cell cycle [139–143]. All these observations are rational isolated from Salvia prionitis lance [114, 115]. Sanguinarine evidence supporting the application of tetrandrine as an is a selective inhibitor of mitogen-activated protein kinase adjunct for cancer chemotherapy or radiotherapy. phosphatase 1 (MKP-1), which is overexpressed in many Activation of glycogen synthase kinase 3β (GSK-3β), tumor cells [116]. The disruption of microtubule assembly generation of ROS, activation of p38 mitogen-activated dynamics [117], the nucleocytoplasmic trafficking of cyclin protein kinase (p38 MAPK), and inhibition of Wnt/beta- D1 and TopII [118], and the induction of DNA damage [109] catenin signaling might contribute to the anticancer effects of also contributes to, at least in part, the anticancer effects tetrandrine [126, 127, 144–146]. Tetrandrine also effectively of this compound. Sanguinarine is a potent suppressor of up-regulates p53, p21, p27, and Fas [123, 124, 145, 147]; NF-κB activation induced by TNF, interleukin-1, phorbol down-regulates Akt phosphorylation, CDKs, and cyclins ester, and okadaic acid, but not that activated by hydrogen [124, 145, 148]; modulates the members of the Bcl-2 family peroxide or ceramide [119]. It also effectively inhibits the including Bax, Bcl-xL, and Bid [147, 148]; activates caspases signal transducer and activator of transcription 3 activation [145, 147]. (STAT-3) [120]; downregulates CDKs, cyclins, MMP-2, and MMP-9 [107, 110]; upregulates p21, p27 [107], and the 2.7. Other Alkaloids with Anticancer Effects. Aside from the phosphorylation of p53 [101]; modulates the members of the aforementioned alkaloids, other alkaloids such as chelery- Bcl-2 family including Bax, Bak, Bid, Bcl-2, and Bcl-xL [101, thrine isolated from Toddalia asiatica (L.) Lam, chelidonine 105, 106]; activates caspases [104–106]; and upregulates isolated from Chelidonium majus L., fagaronine isolated from death receptor 5 (DR-5) [104]. Fagara zanthoxyloides Lam., lycorine isolated from Lycoris, nitidine chloride isolated from Zanthoxylum nitidum (Roxb.) DC., solanine isolated from Solanum tuberosum, sopho- 2.6. Tetrandrine. Tetrandrine (Figure 1), a bisbenzyliso- carpine isolated from Sophora alopecuroides L., trigonelline quinoline alkaloid from the root of Stephania tetrandra, isolated from trigonella foenum-graecum also present anti- exhibits a broad range of pharmacological activities, includ- cancer potentials with diversiform mechanisms [11, 149– ing immunomodulating, antihepatofibrogenetic, antiinflam- 153]. However, reports on the anticancer activities and matory, antiarrhythmic, antiportal hypertension, anticancer underlying mechanism of actions of these compounds are and neuroprotective activities [11, 121]. It generally presents limited. its anticancer effects in the micromolar concentrations. Tetrandrine induces different phases of cell cycle arrest, depends on cancer cell types [122–124], and also induces 3. Discussion apoptosis in many human cancer cells, including leukemia, bladder, colon, hepatoma, and lung [122–130]. In vivo In this paper, we summarized the recent progress of several experiments have also demonstrated the potential value of typical alkaloids with anticancer activities and presented tetrandrine against cancer activity [126, 127, 131]. For exam- some characteristics of these compounds. On the basis of the ple, the survival of mice subcutaneously inoculated with previous studies, alkaloids with anticancer activities reflect CT-26 cells is extended after daily oral gavage of 50 mg/kg diversity at least in three aspects. or 150 mg/kg of tetrandrine [127]. Tetrandrine also inhibits First, the source of alkaloids with anticancer potentials the expression of VEGF in glioma cells, has cytotoxic effect is very extensive. Most of the aforementioned alkaloids are on ECV304 human umbilical vein endothelial cells, and from different families, and the biosynthesis of these com- suppresses in vivo angiogenesis [131]. Tetrandrine-treated pounds is also varied. For example, berberine is isolated from B M P Autophagy Anti-MDR E M P S T B E M P S T Evidence-Based Complementary and Alternative Medicine 5 BE MP S T Antiangiogenesis Anticancer Differentiation BP B: Berberine P: Piperine E: Evodiamine S: Sanguinarine M: Matrine T: Tetrandrine Figure 2: Berberine, evodiamine, matrine, piperine, sanguinarine, and tetrandrine restrain cancer by modulating multiple signaling pathways, resulting in the inhibition of the initiation of carcinogenesis, induction of cell cycle arrest, apoptosis, autophagy, or differentiation, and inhibition of metastasis, angiogenesis, and so forth. Ranunculaceae and roots in phenylalanine and tyrosine, millimole [60]. Therefore, modification of the compound via whereas evodiamine is isolated from Rutaceae and roots in chemical methods may be a good strategy. This observation tryptophan [1]. Second, the pharmacological activities of also indicates that combination therapy probably provides these alkaloids are varied [11, 12, 154]. For instance, piperine an optimal venue for the clinical application of these com- and berberine are used to treat epilepsy and diarrhea, pounds because most of these alkaloids exhibit synergistic or respectively [155, 156], and both of these compounds show enhancement effects when combined with chemotherapeutic anticancer and other pharmacological effects. Third, the drugs in both in vitro and in vivo experiments [95, 136, 157, research focuses of these anticancer alkaloids are also very 158]. different. Research on piperine is usually focused on cancer Second, alkaloids isolated from natural herbs seem to prevention [82, 85], whereas that on most other alkaloids have many targets to realize their multiple pharmacological is mainly focused on cancer chemotherapy, especially on effects (Figure 3), indicating that most of them are “dirty the evaluation of antiproliferative activity [12, 37, 113, 124]. compounds.” These “dirty compounds” are a pressing medi- Figure 2 summarizes the different roles of the aforemen- cal necessity, especially for the treatment of complex diseases tioned six alkaloids to achieve their anticancer effects. such as cancer [159]. However, the discovery of the molecular In addition to their diversity, the anticancer alkaloids also targets and mechanisms of these alkaloids still has a long way have several other characteristics or/and issues which should to go. Recent developments in biology, such as the emergence be addressed. First, the range of alkaloid concentration of the “-omics” fields of study, surface plasmon resonance necessary to elicit the anticancer effects is wide [4, 5, 12, technology, and siRNA, may greatly facilitate researches in 60, 124]. The needed concentration is relatively higher for this area [4, 160–163]. most of the aforementioned alkaloids to produce anticancer Third, most of these alkaloids have poor water solubility effects, compared with the widely used chemotherapeutic and low bioavailability and are hard to reach the specific drugssuchasCPT [5] and vinblastine [4], although both cancer site. In addition to the structural modification, are also naturally derived alkaloids. The concentration of changing the drug delivery system could be another strategy. matrine used to produce anticancer effects even reaches The development of nanotechnology may bring hope to solve B E M Antimetastasis Cell cycle arrest M P S T BE M S T Chemoprevention Apoptosis 6 Evidence-Based Complementary and Alternative Medicine Fas-L Fas-L Piperine Sanguinarine Tetrandrine Berberine Evodiamine Matrine P-gp P-gp DR-5 Fas Cell Piperine Sanguinar S S S S S ine Evodiamine Matrine membr m ane Fas Fas Berberine Tetrandrine NO Akt Cyclin D1 MMP-2 c-Fos GSH p38 MAPK COX-2 ROS PKC MMP-9 CDKs ROS ATF-2 ERK NF-κB NF-κB MMP-9 E2F1 NF-κB STAT3 Cyclin B1 JNK Caspases Caspases MMP-2 p21 Cyclin D1 p27 Wnt CREB Bax p27 Bax CDKs Bax CDKs PKCα p21 Bcl-2 Bcl-2 Caspases Bcl-2 FAK p53 p53 Tubulin MMP-9 GSK3β u-PA cdc25C p27 ERK Cyclin D1 MMP-2 Akt p38 MAPK p21 HIF-1 MKP MKP-1 1 C C Cy y yc c cl l lin D1 in D1 in D1 p27 p27 NA NAT T T Tu ubulin bulin p21 p21 GADD153 GADD153 GADD153 E Ev vo odiamine diamine Ber Berb ber erine-DN ine-DNA A Ber Berb ber eri ine-RN ne-RNA A c co omple mplex x c co omple mplex x Ber Berb be er ri ine ne To Top II p II To Top p I I T T Te el lomer omeras ase e DN DNA damage A damage d Sanguinar Sanguinarine ine N Nuclear membr l ane : Activation or upregulation Inhibition or downregulation Figure 3: The schematic diagram of the molecular machinery and possible targets for the antineoplastic properties of berberine, evodiamine, matrine, piperine, sanguinarine, and tetrandrine. ATF-2: activated transcription factor 2; Bax: Bcl-2-associated X protein; Bcl-2: B-cell lymphoma 2; CDKs: cyclin-dependent kinases; COX-2: cyclooxygenase 2; CREB: cAMP response element-binding; DR-5: death receptor 5; ERK: extracellular signal-regulated kinase; FAK: focal adhesion kinase; Fas-L: Fas ligand; GADD153: growth arrest and DNA-damage- inducible gene 153; GSH: glutathione; GSK3β: glycogen synthase kinase 3β; HIF-1: hypoxia-inducible factor 1; MKP-1: mitogen-activated protein kinase phosphatase 1; MMP-2: matrix metalloproteinase 2; MMP-9: matrix metalloproteinase 9; NAT: N-acetyltransferase; NF-κB: nuclear factor κ-light-chain-enhancer of activated B cells; NOS: nitric oxide synthase; p38 MAPK: p38 mitogen-activated protein kinase; PKC: protein kinase C; P-gp: P-glycoprotein; ROS: reactive oxygen species; STAT-3: signal transducer and activator of transcription 3; TopI: topoisomerase I; TopII: topoisomerase II; u-PA: urokinase-type plasminogen-activator. these problems, and actually, there have been already some berberine for the treatment of diabetes or metabolic syn- successful cases [164, 165]. drome, there is no report about the clinical trial for cancer Fourth, the toxicity of these compounds also cannot prevention or treatment using the aforementioned alkaloids. be ignored. For example, the most common side effects As there is a big jump from experiment researches to clinical of berberine include anaphylaxis, constipation, and skin ones, it is necessary to carry out some clinical anticancer allergies [166]. Berberine can displace bilirubin from serum- trials for these alkaloids, such as berberine and tetrandrine. binding proteins and cause kernicterus, jaundice, and brain In conclusion, for the future work in the field, (1) damage in infants [166–168]. Neurotoxicity, immunotox- the exact anticancer mechanisms of alkaloids should be icity, and reproductive toxicity induced by piperine have further identified using new pharmacological technologies; been reported [169–171], and hepatotoxicity and embryonic (2) the chemical structures of these lead compounds may be toxicity can also be induced by sanguinarine [172, 173]. transformed via pharmaceutical chemistry; (3) the effective Therefore, alkaloids isolated from natural herbs are not combinational therapy methods may be explored; (4) the always safe. The dosages, the routes of administration and effective drug delivery systems need to be developed; (5) the the treatment procedures, among others, are very important. additional clinical anticancer trials for these alkaloids need to The transformation of chemical structures and the applica- be performed. tion of newdrugdeliverysystems mayreducethe toxicities of these compounds. 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