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  Chinese Journal of Natural Medicines  2016, Vol. 14 Issue (1): 7-16  DOI: 10.3724/SP.J.1009.2016.00007
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Cite this article as: 

WANG Chong-Zhi, Samantha ANDERSON, DU Wei, HE Tong-Chuan, YUAN Chun-Su. Red ginseng and cancer treatment [J]. Chinese Journal of Natural Medicines, 2016, 14(1): 7-16.
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Research funding

This work was supported in part by the NIH/NCCAM grants AT004418 and AT005362.

Corresponding author

WANG Chong-Zhi,Tel:(+1)773-702-0166;E-mail:cwang@dacc.uchicago.edu

Article history

Received on: 20-July-2015
Red ginseng and cancer treatment
WANG Chong-Zhi1 , Samantha ANDERSON1, DU Wei2, HE Tong-Chuan3, YUAN Chun-Su1, 4    
1 Tang Center for Herbal Medicine Research, and Department of Anesthesia & Critical Care, The Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, USA;
2 Ben May Department for Cancer Research, The Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, USA;
3 Molecular Oncology Laboratory, Department of Orthopedic Surgery, The Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, USA;
4 Committee on Clinical Pharmacology and Pharmacogenomics, The Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, USA
[Abstract] The ginseng family, including Panax ginseng (Asian ginseng), Panax quinquefolius (American ginseng), and Panax notoginseng (notoginseng), is commonly used herbal medicine. White ginseng is prepared by air-drying after harvest, while red ginseng is prepared by a steaming or heating process. The anticancer activity of red ginseng is significantly increased, due to the production of active anticancer ginsenosides during the steaming treatment, compared with that of white ginseng. Thus far, anticancer studies have been mostly focused on Asian ginseng. In this article, we review the research progress made in the anticancer activities of red Asian ginseng, red American ginseng and red notoginseng. The major anticancer mechanisms of red ginseng compounds include cell cycle arrest, induction of apoptosis/paraptosis, and inhibition of angiogenesis. The structure-function relationship analysis has revealed that the protopanaxadiol group ginsenosides have more potent effects than the protopanaxatriol group. Sugar molecules in ginsenosides inversely impact the antiproliferative potential of these compounds. In addition, ginsenoside stereoselectivity and double bond position also influence the anticancer activity. Future studies should focus on characterizing active red ginseng derivatives as potential anticancer drugs.
[Key words] Red ginseng    Panax ginseng    Panax quinquefolius    Panax notoginseng    Cancer chemoprevention    
Introduction

Cancer is the second leading cause of deathfor both men and women in the United States [1]. The clinical management of cancer invariably involves diverseconventional modalities,including surgery,radiation,and chemotherapy [2]. However,the complex characteristics of human cancers require somealternative management to improve the therapeutic efficacy of conventionaltreatment and the quality of life of cancer patients [3]. Complementary and alternative medicine (CAM) has recently gainedcloser attention for cancer management. CAM covers a wide spectrum of ancientto new-age approaches that purport to expand options for preventing andtreating diseases,including cancer [4]. However,recent surveys indicating a high prevalence of CAM useamong cancer patients also reveal low rates of disclosure to physicians,contributingto the growing concerns about CAM among oncologists [5]. While the treatment outcomes of some CAMs are uncertain,attemptshave been made to conduct controlled clinical studies of CAM approaches tocancer prevention,treatment,and palliation [5]. Therefore,CAM research offers both exciting opportunities andmajor challenges.

To evaluate whetherCAM has become an integral part of American health care,two comprehensivesurveys were conducted by the National Institutes of Health in 2002 and 2007.In the 2002 survey,of 31 044 adults interviewed,36.0% had used some forms ofCAM in past 12 months [6]. In the 2007 survey,of 23 393 adults interviewed,38.3% had usedCAM in the past year [7]. The most commonly used CAM were natural products (17.7%),deepbreathing exercises (12.7%),meditation (9.4%),chiropractic or osteopathicmanipulation (8.6%),massage (8.3%),and yoga (6.1%). Thus,naturalproducts,including herbal medicines,are the most commonly used CAM modalityin the United States [7].

Herbal medicineshave been the major source of therapy in many traditional medical systems andhave been used clinically for the treatment of a variety of diseases [8]. Among these herbs,ginseng has a long history and is one of theworld’s most widely used medicinal plants today [9]. Panax L. is a small genus of the family Araliaceae. Nearlyall species in the genus Panax,such as Panax ginseng C. A.Meyer (Asian ginseng),Panax quinquefolius L. (Americanginseng),and Panax notoginseng (Burk.) F. H. Chen (notoginseng),are important herbs used to treat different medicalconditions [10,11]. Asian ginseng and notoginseng are considered Chinese herbalmedicines,and American ginseng is one of the most commonly used botanicals inNorth America.

Asian ginseng iscommercially available as white and red ginseng in China,Korea,and Japan.White ginseng is prepared by air-drying after harvest. If fresh ginseng isprocessed by steaming,its color changes to red,and thus the product is calledred ginseng [12]. Asian ginseng has been extensively studied and used in the clinicand in general population. Several epidemiological studies have suggested thatAsian ginseng can prevent or treat many types of human malignancies [13]. In contrast,anticancer studies of American ginseng andnotoginseng are limited and the results are mostly experimentally based.Published studies suggest that red ginseng has more potent anticanceractivities than white ginseng [14,15].

In this review,research progresses made in cancer prevention and therapy of red ginseng aresummarized. In addition to red Asian ginseng,anticancer related studies on recentlydeveloped red American ginseng and red notoginseng are also discussed. Becauseof the obvious chemical degradation and conversion of original ginsenosides tonew compounds during the steaming process,the chemical composition of steamedginseng is quite different from that of untreated ginseng. The anticancer-relatedmechanisms of red ginseng compounds,and structure-functional relationship ofginsenoside derivatives are also discussed,which may facilitate thedevelopment of these compounds as effective anticancer agents in the future.

Commonlyused ginseng herbs Asian ginseng (Panax ginseng C. A. Meyer)

Asian ginseng is ahighly valued herb distributed in Northeastern China,Korea,Far Eastern Russiaand has gained popularity in the West. The name ginseng isderived from a Chinese term referring to the “man-like” shape of the root. Thegenus Panax,means “cure all” in Greek. Traditionally,the ginseng root,availablein white or red,is used. White ginseng is prepared by air-drying,and redginseng is prepared by a steaming or heating process [12]. The leaf,berry and other parts of ginseng are also medicinal sources.

Asian ginsengcontains different constituents,including ginsenosides,polysaccharides,peptides,polyacetylenic alcohols,and fatty acids [16]. Most of the pharmacological actions of ginseng can be attributedto ginsenosides [10, 17]. Many ginsenosideshave been isolated,and novel structures continue to be reported [10].

Ginseng root hasbeen used for centuries in Oriental medicine as a panacea that promoteslongevity. The efficacy of ginseng was discovered in the West by the 18thcentury,and the study of ginseng has a long history. Many studies supportedthe beneficial effects of Asian ginseng. Recently there has been a renewedinterest in investigating ginseng pharmacology using biochemical and molecularbiological techniques. Pharmacological effects of ginseng have beendemonstrated in the CNS and in cardiovascular,endocrine,and immune systems [16, 18, 19]. In addition,ginseng and its constituents have been ascribed antineoplastic,antistress,and antioxidant activities [20,21,22].

Asian ginseng and its chemical constituentshave been tested for their inhibitory effect on human cancers. Severalinvestigators found anticancer properties of ginseng,with ginsenosides Rg3 and Rh2 as the active anticancer saponins [14]. Ginseng extracts were also found to inhibit the growth of breastcancer cells [23]. Our group has investigated the effects of botanical extracts onreducing chemotherapeutic side effects and found that ginseng can attenuatecisplatin-induced nausea and vomiting [24,25]. Additionally,the ginseng extract enhanced the antiproliferationeffect of 5-fluorouracil (5-FU) on human colorectal cancer cells,suggestingthat it possesses its own anticancer activity [26,27].

American ginseng (Panax quinquefolius L.)

American ginseng is distributed in theeastern temperate forest areas of North America from southern Quebec to Minnesotain the north to Oklahoma,the Ozark Plateau and Georgia in the south. The partof the plant commonly used in remedies is the root. It was first introduced inthe New Compilation of Materia Medica (Ben Cao Cong Xin) by WUYi-Luo in 1757. In the western world,it was recorded in Quebec,Canada,byFather Lafitau in the early 18th century,and since then has generated a lot ofinterest [28].

It is believed thatthe bioactive constituents of American ginseng extract are ginsenosides,whichare present in different parts of the plant [10]. A couple dozen of ginsenosides,such as Rb1,Rb2,Rc,Rd,Re,Rg1,and Rg3,have been identified in American ginseng roots [29,30]. Ginsenosides are also distributed in other parts of the herb,including the leaves,flowers and berries [10, 31].

American ginsengis reported to have a wide range of therapeutic and pharmacologicalapplications,such as tonic,antiaging,immunomodulating,anti-fatigue,antidepressant,antidiabetic and antitumor activities [16, 32]. Severalprevious studies of American ginseng focused on the effects on thecardiovascular system,such as anti-ischemic,antiarrhythmic andantihypertensive effects [28, 33]. These pharmacologiceffects are,to a significant extent,considered to be linked to theantioxidant properties of the herb. Because there is no typical antioxidantstructure in ginsenosides,it was suggested that ginsenosides scavenge freeradicals with a protection mechanism for the antioxidant-related protein orenzymes [34].

The effects ofAmerican ginseng on cancer treatment and side-effect management were evaluated.These observations include in vitro and in vivo anticanceractivity alone and in combination with chemotherapy [35],potential mechanisms of action of the anticancer effect,chemopreventive effect supported by epidemiologic data,and effects onpreventing or alleviating chemotherapy-induced side effects [25].

Notoginseng (Panax notoginseng (Burk.) F. H. Chen)

Notoginseng is aChinese herbal medicine that has a long history of use in China and other Asiancountries. This herb is distributed in Southwestern China,Burma,and Nepal.Notoginseng is cultivated commercially in the southwestern regions of China,especially in Yunnan Province. The portion of the plant commonly used inremedies is the root,which is dug up after the fruit has ripened [36].

The earliestscientific description of notoginseng was in Materia Medica (Ben CaoGang Mu),a dictionary of Chinese herbs,written by LI Shi-Zhen (1518−1593 AD). In Materia Medica,notoginseng was called “more valuable than gold”,indicating the significanceof this herb in traditional Chinese medicine [37].

The main bioactive compounds in notoginsengare dammarane saponins,commonly referred to as ginsenosides andnotoginsenosides. Oleanane-type saponin,present in Asian ginseng and Americanginseng,is not found in notoginseng. Over 60 saponins have been isolated fromthe notoginseng plant. Most of them belongto the protopanaxadiol group,whileothers belong to the protopanaxatriol group [37,38]. Ginsenosides Rb1,Rg1,and Rd and notoginsenoside R1 are the main saponins in the notoginseng roots [39].

Notoginseng is regarded as the emperor herbin the treatment of different types of wounds because it is a favorite medicinefor both internal and external hemorrhage [40]. Notoginseng can also decrease blood pressure,improve blood supplyand protect against shock,and protect the cardiova­scular system and brainvasculature [36, 41]. Itsprotective mechanism is partly due to protection against damage by oxygen freeradicals,and also by binding to the estrogen receptor,as ginsenosides sharemany of the protective actions of estrogen in various physiological systems [42,43]. Notoginseng extracts were also found to possess the capacity toadjust energy metabolism and treat diabetes [44].

Some studies alsoshowed that notoginseng has antitumor effects [45,46,47]. Recently,our group found that notoginseng extract can increasethe effects of 5-FU,a commonly used cancer chemotherapeutic agent. Since it iswell known that 5-FU has cytotoxic effects on primary cells,the synergisticeffect between notoginseng and 5-FU makes it possible to reduce the dose of5-FU in combination with notoginseng extract and thereby further decreasedose-related toxicity [48].

Steam processing changes ginsenoside structures

In Asia,ginseng root is air-dried into white ginseng or steamed at 100 ºCfor several hours to produce red ginseng [49,50]. It is believed that redginseng is more pharmacologically effective than white ginseng. The differencesin the biological effects of white and red ginseng are attributed to the significantchanges in ginsenosides from the steaming treatment. Compared with white Asianginseng,red ginseng has stronger anticancer activities [14],due to a relatively high content of the ginsenoside Rg3. It seemslikely that the steaming process or heat-treatment of ginseng is a goodapproach to transfer inactive ginsenosides to active anticancer compounds suchas ginsenoside Rg3,Rh1,Rh2,and their aglycones [49].

The optimum steaming condition for Americanginseng is at 120 ºC for 4 h [51]. Because of obvious chemical degradationand conversion of the original saponins to new compounds during the steamingprocess,the chemical composition of steamed American ginseng is quitedifferent from that of the untreated ginseng. After steaming,the originalpolar ginsenosides decrease considerably and the less polar ginsenosidesincrease [51,52]. The less polar compounds are not detected or arepresent in small amounts in untreated ginseng.

Constituent changes of notoginseng aftersteaming treatment have also been reported. After steaming treatment,thecontent of major ginsenosides Rb1,Rg1,Rd and notoginsenoside R1 decreased,while that of less polar ginsenosides increased. The major markers in rednotoginseng include three groups of epimers or geometric isomers,namely 20(S)-Rg3 and 20(R)-Rg3,Rk3 and Rh4,Rk1,and Rg5 (Fig. 1). These compounds are not detected or are only presentin trace amounts in unsteamed notoginseng [15, 39]; this trendis very similar to what occurs after the steaming of Asian ginseng and Americanginseng.

Fig. 1 Effects of steaming treatment on protopanaxadiol groupginseng saponin conversion and anticancer activity. (A) Ginsenoside structuralchanges during steaming treatment. Abbreviations for sugar residues: Glc, β-d-glucose; Ara(Pyr), α-l-arabinose(pyranose);Ara(Fur), α-l-arabinose(furanose); and Xyl, β-d-xylose. (B)Ginsenoside derivatives have different anticancer activities. Sugar moleculenumbers have an inverse impact on anticancer potential

In three ginseng plants,representativeginsenosides are classified as protopanaxadiol (PPD) and protopanaxatriol (PPT)groups. For ginsenosides in the PPD group,e.g. ginsenosides Rb1,Rb2,Rb3,Rc,and Rd,it is easy to selectively eliminatethe carbon-20 sugar chain to produce 20(S)/(R) Rg3. The generatedcontent of 20(S)-Rg3,however,is higher than that of 20(R)-Rg3.Due to the presence of the chiral carbon in carbon-20,there are several groupsof 20(S) and 20(R) epimers in white and red ginsengs like 20(S)/20(R)-Rg2,20(S)/20(R)-Rg3,and 20(S)/20(R)-Rh2 [10]. In particular,20(S) and 20(R)are epimers of each other,depending on the position of the hydroxyl (OH) group on carbon-20. This epimerizationis known to be produced by the selective attack of the OH groupafter the elimination of the glycosylresidue at carbon-20 during the steaming process [53]. Rg3 could be further transformed totwo geometric isomers,namely Rk1 and Rg5,by dehydration. The formed Rk1 andRg5 represent positional isomers of the double bond at carbon-20(21) or carbon-20(22)(Fig. 1). It was found that the epimers and geometric isomers presented similarretention times under most liquid chromatographic conditions. 20(S)ginsenoside was usually eluted earlier than its relevant 20(R) epimer,and 20(21)-geometric isomers were eluted earlier than their relevant20(22)-isomers [54]. Only a low abundance of Rh2 wasobserved in red ginseng,implying the elimination of carbon-3 sugar residue isrelatively difficult in the steaming process.

On the other hand,the PPT group ginsenosides (R1,Rg1,Rf,and Re) tend to lose (20)glc residuefirstly and subsequently its terminal sugar unit at carbon-6 to form 20(S)/20(R)-Rg2and/or Rh1. Rh1 is further converted to Rk3 and Rh4 by dehydration atcarbon-20. The above results suggested that the elimination of sugar chains atcarbon-20,then at carbon-6 or at carbon-3,and then the subsequent dehydrationreaction at carbon-20 are commonly observed in the steaming process [55]. The carbon-20 sugar moiety is the most thermally unstable,followed by carbon-6 and then carbon-3 sugar moieties.

Other than saponins,ginseng also contains other constituents,including flavonoids,polyacetylenes,phytosterols,essencial oils,acids,polysaccharides,nitrogen-containing compounds and vitamins. During thesteaming process,the structures of these compounds could also be altered.However,previous studies often only focused on ginseng saponins. Thestructural changes of other compounds and subsequent changes in theirbiological activities remain largely unknown,which need to be evaluatedin the future studies.

Anticancer activities of steamed ginseng

Ginseng has many reported health benefits [16]. Regarding its anticancer effects,a case-controlstudy on over a thousand Korean subjectsshows that long-term ginsengconsumptionis associated with a decreased risk formany different cancers,compared with those who do not consume ginseng [56,57]. It also suggested that ginseng has a non-organspecific preventive effect against cancers [13]. It has been reported that the anti-carcinogeniceffects of white ginseng are more prominent after being heat-treated or steamed[58]. The enhanced anti-carcinogenic effects ofred ginseng are linked to the inhibition of lipid peroxidation and regulationof the targets involved in the cytochrome P450 signaling pathway [59].

Steam-processingcan yield very high amount of active ginsenosides.More specifically,our group has performed a systematic comparison of the ginsenosidesand anticancer activities among the white (air-dried) and red (steamed) rootsof Asian ginseng,American ginseng,and notoginseng,and observed that,due tothe conversion of the original polar ginsenosides in white ginseng to novel,less polar,degradation compounds in red ginseng,white ginseng produces weakantiproliferative effects,while red ginsengs exhibits a significant increasein antiproliferative and pro-apoptotic effects,with rednotoginseng exhibiting the greatest anticancer activities [15, 51, 52, 60]. The next logical step in the study of red ginsenganticancer activity should be to systemically compare the differences inchemical composition among three red ginsengs and reveal the linkage betweenginsenoside derivatives and their related anticancer activities.

The main active components of red ginseng for cancer prevention arebelieved to be ginsenosides Rg3,Rh2,Rg5,and PPD,and these compounds worksingularly and/or synergistically [58,61]. Among these ginsenosides,Rg3 and Rg5 showsignificant reductions in lung tumor incidence when examined in a medium-termlung carcinogenesis mouse model [58]. Additionally,red ginseng workssingularly as well as synergistically with chemotherapeutic agent 5-FU to exertantiproliferative effects on a human colorectal cancer cell model [26]. Epirubicin and paclitaxel are twoimportant chemotherapeutic agents widely used to treat a broad spectrum ofcancers. Because of their significant adverse effects,developing adjuvantagents to reduce their adverse effects are urgently needed. Red ginsengsignificantly potentiated the anticancer activities of epirubicin andpaclitaxel in a synergistic manner; thus,their dose and the dose-relatedadverse events could be reduced. Red ginseng treatment activated caspases 3 and9,increased the mitochondrial accumulation of both Bax and Bak that led to anenhanced cytochrome c release,and induce apoptosis [62]. In another recent study,the protectivemechanism of red ginseng in anticancer drug-induced toxicity was observedthrough the regulation of NF-κB activities [63].

Along with its anti-carcinogenic and antitumor activities,red ginsengalso has anti-inflammatory and antioxidant activities,which also contribute toits chemopreventive effects. Recently,the important link between inflammationand carcinogenesis has begun to be elucidated,and it is thought that redginseng may exert some of its cancer chemopreventive effects by stoppinginflammatory carcinogenesis [64].There are several key molecularplayers that link inflammation tocarcinogenesis,including prostag­landins,cytokins,chemokines,angiogenicgrowth factors,and free radicals. These factors,coupled with other risks andprocesses,lead to increased mutations and altered functions of important enzymesand proteins,which contribute to the carcinogenic process. Red ginseng isthought to attenuate inflammation-associated carcinogenesis through a varietyof pathways by scavenging reactive oxygen species,reducing Cox-2,iNOS,andNF-κB,inhibiting proliferation,andinducing a dual anti-angiogenic effect on carcinogenesis [64]. In summary,red ginseng exerts its anticancereffects through a variety of pathways and can be used alone or in combinationwith other chemotherapeutic agents.

Red ginseng compounds and anticancer mechanisms

In recent years,as techniques have been developed for chemical purification and structuralidentification,novel ginseng saponins continue to be characterized. In steamedred ginsengs,ginsenosides Rg3,Rh2,Rg5,Rk1,Rk3,and Rh4 and aglycones PPDand PPT have shown stronger anticancer potential than their parent compounds inuntreated white ginseng [55]. Their anticancer potentials were observed by in vitro cellantiproliferative determinations and verified by in vivo antitumorevaluations. Anticancer related mechanisms were found to be linked with cellcycle arrest,induction of apoptosis and paraptosis,and inhibition ofangiogenesis.

Cancer cells lacknormal growth controls,exhibit loss of cell cycle control,and have unlimitedreproductive potential and growth-signal self-sufficiency. Any compounds aimedat controlling these processes would be beneficial in suppressing the progression of cancers [65]. Several ginsenosides including Rg3,Rh2,and PPD have been shown to block the cell cycleprogression. G1 phase or G1/S boundary appears to be arrested via differentmechanisms [66,67]. Rh2 blocks the cell cycle at the G1/S boundary by selectivelyinducing the expression of p27Kip1 [68]. Rg5 and Rs4 (acetylated Rg5) achieve similar effects byselectively elevating the levels of p53 and p21WAF1 [69]. Recently,our group observed that PPD arrested cancer cell cycleat G1 phase,which is mediated by targeting NF-κB,JNK,and MAPK/ERKsignaling pathways [70].

Apoptosis isprogrammed cell death involving the activation of caspases through either amitochondria- dependent cell intrinsic or mitochondria-independent cellextrinsic pathway. Currently,many researches are focused on exploring novel compounds that can regulate cellproliferation and apoptosis in order to elucidate new candidates forcancer therapy [71]. Red ginseng and active ginsenosides target signaling intermediatesin apoptotic pathways. It was found that red ginseng compounds Rg3,Rh2 and PPDalter the mitochondrial membrane permeability,promote the release of cytochrome c into the cytosol,activate caspaseproteases,and cleave poly ADP ribose polymerase [72,73]. Theactivity of cyclin-dependent kinases also may be associated with the depolarization of mitochondrial membrane potentialduring ginsenoside-induced apoptosis. In the death receptor- mediated pathway,ginsenosides increase the expression of the DR4 death receptor and activatecaspases 8 and 3 [74]. By regulating the interactions between p53 and DR4/DR5,our groupobserved that the tumor necrosis factor-related apoptosis-inducing ligand(TRAIL) pathway is associated with PPD’s cancer chemotherapy [75].

In addition toapoptosis,several types of caspase independent programmed cell death have beenidentified,including paraptosis,which ischaracterized by cytoplasmic vacuolization,lacks apoptotic morphology,and does not respond to caspase inhibitors [76]. Recently,our group observed that ginsenoside Rh2 and PPD inducedcell death is partially dependent on caspase 3 activation. Interestingly,wealso found that Rh2 and PPD induce a significant level of cytoplasmic vacuoleformation,which is characteristic of paraptosis. Rh2 and PPD treatmentactivated the NF-κB pathway to protect the cancer cells from cell deathwhile simultaneously activating two different cell death pathways. In addition,Rh2 and PPD activated the p53 pathway,which contributed to the induction ofboth apoptosis and paraptosis-like cell death [77,78].

Angiogenesis isthe process by which new blood vessels are formed from pre-existing structures.Since the uncontrolled growth of solid tumors is closely related to tumor angiogenesisby delivering nutrients and oxygen for the survivalof tumor cells,adequate control of tumor angiogenesis has been an attractivetarget for tumor therapy [79]. Red ginseng inhibits tumor growth by influencing neovasculari­zationand the angiogenesis-related properties of endothelial cells. Endothelial cellmarkers,such as CD-31,are often used to measure angiogenesis [80]. Ginsenoside Rg3 inhibits proliferation,formation of capillarytube,and chemoinvasion of endothelial cells induced by vascular endothelialgrowth factor [81]. The angiosuppressive effect of Rg3 may be related to the differentialregulation of matrix metalloproteinase (MMP)-2 and -9 activities [81]. Rg3 effectively abrogated the vascular endothelial growth factor(VEGF) dependent on neovessel formation and attenuated endothelial progenitorcell mobilization,leading to delayed tumor progression and tumor angiogenesis [82].

Other pathwayssuch as those that prevent the metastatic spread of cancer or reduceinflammatory responses are also reported to be part of the chemopreventive andtherapeutic effects of red ginseng compounds [83,84].

Structure-activity relationship of ginsenosides

Ginseng saponinsbelong to a family of triterpene glycosides or triterpene saponins. Ginsengsaponins (except ginsenoside Ro) possess the four trans-ring rigid steroidskeleton,with a modified side chain at carbon-20. Sugar residues are attachedto the -OH of the aglycone. Ginseng saponins can mainly be classified asprotopanaxadiol group and protopanaxatriol group [10].

For theprotopanaxadiol group,sugar residues are attached to the β-OH atcarbon-3 and another -OH at carbon- 20 of the aglycone,such as ginsenosideRb1,Rc,Rd,Rg3 and Rh2. For the protopanaxatriol group,sugar residues are attachedto the α-OH at C-6 and another -OH at carbon-20 of the aglycone,such asginsenoside Re,Rg1,Rg2,Rh1 and notoginsenoside R1 [10, 36].

Structure-activityrelationship elucidates the relations between chemicalstructure and their pharmacological activity for a series of compounds. The anticanceractivities of ginseng saponins are correlated with the type of aglycones andsugar residues. Sugar molecules within a ginsenoside have a high impact ontumor cells. Anticancer activities increase with the decrease of sugar number(Fig. 1). Ginsenosides with three or more sugar molecules (e.g.,Rb1,Rb2,Rb3,Rc,and Rd) show no or very weak antiproliferative effects [29, 55].Ginsenosides Rg3,Rg5 and Rk1 (two sugars),Rh1,Rh2,Rh3,Rh4,Rk2,and Rk3(one sugar),PPD and PPT (no sugar) inhibit different types of cancer cells [55]. Interesting,during the steaming process,the length of sugarmoiety in ginsenoside was reduced,thus increasing its anticancer activities.

Differences insugar linkage positions may influence biological responses. In a comparasion ofsugar moiety connected with the postions of carbon-3 or carbon-6,the carbon-6substituent differentiates the two groups of ginsenosides structurally.Ginsenoside Rh2 (PPD type) and Rh1 (PPT type),which possess a glucose linkageat carbon-3 and carbon-6 respectively,havesimilar chemical structures,but the anticancer effect of Rh2 is stronger thanthat of Rh1 [85]. With a sugarsubstitute at carbon-6,the anticancer activity of ginsenosides is attenuatedcompared to the activity with linkages at carbon-3 or carbon-20. Molecularmodeling and docking confirm that any sugar moiety at carbon-6 increases thesteric hindrance of these molecules to target proteins [86]. Steric hindrance blocks entrance into the extracellular bindingpocket for binding to their targets,thus significantly reducing the anticanceractivities of ginsenosides. Overall,the protopanaxadiol group ginsenosideshave more potent effects than those of the protopanaxatriol group. Theanticancer potency of ginsenosides was found to be in the order: carbon-3 >carbon-6 > carbon-20 [55].

20(S) and20(R) are stereoisomers of each other that depend on the positionof the carbon-20 hydroxyl in ginsenosides. 20(S)-OH is geometricallyclose to the carbon- 12 hydroxyl of ginsenosides. 20(R)-OH is far fromthe carbon-12 hydroxyl. The different stereochemistries of the 20(R)-and 20(S)-ginsenosides produce different pharmaco­logical effects.Although 20(S) and 20(R)-Rg3 show similar activity,for the pairof PPD ginsenosides,20(S)-Rg3 has more significant potentantiproliferative effects than 20(R)-Rg3,suggesting that 20(S)-ginsenosideshave stronger anticancer potential than their 20(R)-stereoisomer [87,88].

In addition,theposition of the double bond also influences anticancer activities. In redginseng,rare ginsenosides with a dehydroxylated structure are identifiedduring the steaming process. Ginsenosides Rk3/Rh4,Rk1/Rg5 and Rk2/Rh3 are thedehydroxylated products of Rh1,Rg3,and Rh2 at carbon-20,respectively. Arecent report has indicated that ginsenosides Rk1 and Rk3 with the double bondat C20-21 show higher anticancer effects than Rg5 and Rh4 with a double bond atC20-22 [55]. Thus,ginsenosides with a double bond at C20-21 exhibit moreeffective anticancer activities than those at C20-22.

Conclusions

Ginsengs,including Asian ginseng,American ginseng and notoginseng,are some of the mostcommonly used herbal medicines. The investigations of the effects of ginsengsin cancer chemoprevention and therapeutics have attracted researchers’attention in past several decades. Compared to unsteamed white ginseng,theanticancer activities of red ginseng are significantly increased due to majorginsenosides with low anticancer activity such as Rb1,Rg1 and Re beingconverted to active anticancer ginsenosides such as Rg3,Rk1,Rh1,and Rh2. Ginsengs are saponin-rich botanicalsand steam-processing can yield a very high amount of active ginsenosides. Basedon the above discussion,the emphasis of future studies should be placed oncharacterizing active red ginseng compounds in relation to its anticanceractions. In addition,it is worthy further exploring the systemic differencesin chemical compositions among the three red ginsengs and the linkage betweenginsenoside derivatives and their antitumor potential. Since ginseng alsocontains other compounds in addition to saponins,how the structural changes ofother ginseng compounds influence their anticancer effects needs to befurther characterized. Nevertheless,the revealed structure-activityrelationship provides important information for further semi-synthesis ofginsenoside derivatives for discovery of novel anticancer drugs.

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