Annual advances in traditional medicine for tumor therapy in 2019

Xue Yang,Xin-Yuan Luan

1Department of Medical Oncology,Tianjin Medical University General Hospital,Tianjin 300052,China; 2Department of Hepatobiliary and Pancreatic Surgery(3),Tianjin NanKai Hospital,Tianjin 300100,China.

Abstract

Keywords:Traditional medicine,Traditional Chinese medicine,Tumor,Phytochemicals,Formula

Background

An estimated 18.1 million new cases and 9.6 million deaths were attributed to cancer globally in 2018 [1].The most predominant tumor types with the highest incidence are lung cancer,breast cancer,prostate cancer,and colorectal cancer,whereas lung,colorectal,stomach,and liver cancers result in the highest number of tumor-related deaths [2].The general treatment methods for cancer include surgery,chemotherapy,radiotherapy,targeted therapy,endocrinotherapy,and immunotherapy.An operation is the initial course of treatment for early tumor patients.However,many tumor patients are diagnosed at an advanced stage and have lost the opportunity to use surgical therapy.Therefore,a combination using a multidisciplinary treatment protocol is the burgeoning new trend and appears to show efficacy as a new tumor therapy.Traditional medicine,especially traditional Chinese medicine (TCM),is popular and indispensable as a comprehensive therapy for cancer worldwide.Numerous studies have indicated that TCM,in combination with chemo-,radio-,or as a targeted therapy,may enhance the efficacy,diminish the side effects or complications caused by these therapies [3],and improve the patients’overall quality of life[4].

During 2019,there were a great number of published articles focusing on traditional medicine used as a cancer therapy.The current study summarizes the research progression and trends of several types of traditional medicine articles used for tumor therapy released in 2019,particularly TCM.Statistical analysis of the annual publications that use traditional medicine for tumor therapy in different countries is depicted in Figure1A.China contributed about 3,300 papers in this field in 2019,followed by the United States and the United Kingdom.Moreover,China has maintained amicable,cooperative relations with other countries (Figure1B).Most of the papers published in journals this year primarily focused on traditional medicine.The majority of articles were from theJournal of Ethnopharmacology,which contributed about 132 papers in 2019 (Figure2).We further analyzed the influence of journals and found that the top three comprehensive influential journals arePhytomedicine,European Journal of Medical Chemistry,and theBMC Complement Alternative Medicine(Table1).

Traditional Chinese medicine

Compared with other traditional medicines,TCM is one of the most popular types of treatments in the world,particularly in the field of tumor therapy.According to statistics from 2019,around 3,000 articles focused on this field.We can see that most of these studies covered cell apoptosis,which was ranked first followed by breast cancer,inflammation,colorectal cancer,and hepatocellular carcinoma,via keyword analysis (Figure3).The anti-tumor effects elicited by the active ingredients and the TCM formulas were the main focus of research in 2019.

Figure1 Analysis of country distribution and the cooperation relationship in the field of traditional medicine on tumor therapy.A.Analysis of the annual publications reporting traditional medicine on tumor therapy from different countries.We searched in the PubReminer (https://hgserver2.amc.nl/cgi-bin/miner/miner2.cgi) with the keywords traditional medicine AND cancer OR tumor from 2019/01/01 to 2019/12/31 to analyze the country distribution.B.Analysis of the relationship between different countries in the field of traditional medicine on tumor therapy.We searched the Web of Science using the keywords traditional medicine AND cancer OR tumor from 2019 to the present.Then we downloaded the retrieved results and put them into Bibliometric(https://bibliometric.com/results.html)to analyze the cooperation between different countries.

Figure2 The top 17 journals of publications in the field of traditional medicine on tumor therapy in 2019.The PubReminer (https://hgserver2.amc.nl/cgi-bin/miner/miner2.cgi) with the keyword as traditional medicine AND cancer OR tumor from 2019/01/01 to 2019/12/31 was used to analyze the journal’s contribution.

Figure3 The top ten keywords in traditional Chinese medicine on tumor therapy.We searched in the PubMed database with the keywords traditional Chinese medicine AND cancer OR tumor from 2019/01/01 to 2019/12/31 to analyze the keyword contribution.

Table1 The influence of the top 10 journals

Active ingredients

The anti-tumor molecular mechanisms involved in the active ingredients of Chinese herbal medicine have not yet been explicated.In this article,we have primarily introduced the research progression of several representative natural phytochemicals,such as polyphenols,polysaccharides,saponins,and alkaloids.These phytochemicals have been studied in detail,and their administration is demonstrated to exhibit anti-tumor effects for cancer via multiple mechanisms[2,5].The anti-tumor effects of the polyphenol compounds contained in the natural medicines were an important topic of study in the past year.

Polyphenols.Polyphenols are widely distributed natural compounds from the plant kingdom,including fruits,vegetables,and cereals [6].The polyphenolic structure makes the polyphenol capacity to inhibit reactive oxygen species production,is a fact that is involved in a wide range of key cellular processes,affecting several molecular mechanisms,altered in the tumor cells.Flavonoids,curcumin,and resveratrol all belong to the polyphenolic substances,and their anti-tumor effects have been widely reported for years.

Flavonoids.Natural flavonoid is a type of polyphenol class and comprised of a large group of low molecular weight substances [7].The chemoprevention effects of flavonoids were widely studied in 2019 [8].Intake of flavonoids is associated with a lower risk of cancer,including breast cancer [9],gastric cancer [10],and bladder cancer[11].However,we should also note that not all kinds of flavonoids resulted in a reduced cancer risk according to these studies.

Many Chinese herbal medicine-derived phytochemicals belong to the flavonoids,such as baicalein (fromScutellaria baicalensisGeorgi),genistein (Genista tinctoria),and silibinin (fromSilybum marianum).Baicalein is an active extract of the root ofScutellaria baicalensisGeorgi and studies have shown that baicalein is a potent inhibitor against breast cancer [12,13],gastric cancer [14],non-small cell lung cancer [15],hepatocellular carcinoma [16],and cervical cancer [17].Ma CY et al.used network pharmacological and microarray data to reveal the therapeutic mechanism of action for baicalein in liver cancer at a systemic level.They found that baicalein might exert therapeutic effects against liver cancer through a protein-protein interaction network involving TP53,CDK1,HSPA1A,and HSPA1B[18].

Genistein is a type of phytoestrogens widely found in foods and herbal medicines.A recent review summarized the molecular mechanisms of genistein using diverse cancer models [19].In addition,one study showed that the level of serum genistein was associated with a colorectal cancer prognosis.However,this association might be differential using adjuvant chemotherapy [20].Although genistein is safe and possesses anticancer efficiency,it has been proven in numerous preclinical investigations,that it is not applicable to all people.One reason is that genistein binds to the estrogen receptor(ER),including ERα and ERβ,and reportedly is closely related to breast cancer[21].The damaging role of genistein in breast cancer may be related to the expression level of ERα/ERβ.Some research has showed that genistein may be counterproductive in those breast cancer patients with a high ERα/ERβ ratio when they have received anticancer treatment [22].Liu R et al.found that the ERβ pathway deficiency might enhance genistein-cisplatin bioactivity via the downregulation of P53 [21].Another review has explored the relationship between genistein and breast cancer and shown that the intake mode and metabolic characteristics of genistein,as well as the menopausal status,ER expression pattern,and gene mutations of the patient,are important factors that should be included when discussing the bioactivities of genistein.In addition,Wang YL observed that genistein upregulated the proliferation and G1-S transition of ovarian cancer OVCAR-5 cells[23].

Silymarin is a flavonoid complex extracted from the seeds,and the fruit of the milk thistle plantSilybum marianumand silibinin is the main component of silymarin [24].Silibinin has demonstrated activity against many cancers,such as breast cancer [25,26],pancreatic cancer [27],hepatocarcinoma [28],and prostate cancer[29].

Curcumin.Curcumin,derived fromCurcuma longaL.(turmeric rhizomes),is a famous polyphenols and has received great attention as an antioxidant,anti-inflammatory,and anticancer agent [30,31].Turmeric is a plant that has been used for thousands of years in Asia,especially in the Vedic culture in India,where it is frequently used as a culinary spice or a dye and represents a component of TCM and other medical cultures [32].Over the past decades,the chemoprevention and anti-tumor effects of curcumin have been studied worldwide.In 2019,the anti-tumor effects of curcumin,as a single ingredient [33],and in combination with chemotherapeutic agents [34-36],remained the focus of studies with at least 600 articles published.The top keywords used for curcumin focused on apoptosis,breast cancer,drug delivery,inflammation,and oxidative stress(Figure4).

The primary mechanisms of action via which curcumin exhibited anticancer activity include the following inducing apoptosis [37,38],inhibiting proliferation [39,40],regulating cell metabolic profiling [41],epigenetic modification regulation [42],regulating noncoding RNAs [43],regulating the immune system[44,45],and inhibition of the invasion of tumors [46,47].A wide array of studies have reported that the anti-tumor activity of curcumin against breast cancer [48],lung cancer [49],esophageal cancer [50],head and neck squamous cell carcinoma [51,52],colorectal cancer [53],prostate cancer [39],cervical cancer [54],ovarian cancer and brain tumors [55,56],showing a great capability for targeting multiple cancer cell lines.In addition,a great number of clinical trials using curcumin as a single ingredient for cancer therapy and in combination with chemotherapeutic agents has been completed or is under way[57,58].

Figure4 The top ten keywords for curcumin used in tumor studies.We searched in the PubMed with the keywords curcumin AND cancer OR tumor from 2019/01/01 to 2019/12/31 in order to analyze the contribution of these keywords.

During the study using keywords for curcumin,more studies focus on the drug delivery of curcumin.Curcumin generally possesses poor bioavailability;thus,curcumin is developed into several dosage forms or drug delivery ways such as liposome curcumin[59],Hybrid curcumin-phospholipid complex-near-infrared dye oral drug delivery system [60],microsphere or even into the synthesis of curcuminoid analogs are used to improve the anticancer effects of curcumin.In addition,many curcumin analogs have been developed and studied for their anti-tumor effects[61-65].

Resveratrol.Resveratrol is a well-known plant polyphenol that is abundantly present in knotweed and grapes and has been proven to provide antiglycation,antioxidant,anti-inflammatory,neuroprotection,anti-aging,and anticancer effects[66].Food sources of resveratrol include wine,berries,and peanuts.Resveratrol has been demonstrated to modulate a number of signaling pathways that are involved in carcinogenesis [67].Resveratrol exerts tumor-inhibitory properties by inhibiting tumor cell proliferation [68,69],inducing apoptosis [70],reversal of epithelial-to-mesenchymal transition [71-73],inhibition of cell adhesion [74],induction of p53 stability [75],inhibition of steroid receptor signaling[76],regulation of lipid metabolism [77],regulation of noncoding RNAs [78],epigenetic regulation [79],and enhancement of chemotherapeutic agents [80,81].Furthermore,several studies have focused on the synergetic tumor-inhibitory effects of curcumin and resveratrol[82-84].

Although the laboratory and clinical evidence for resveratrol is well documented,rapid metabolism,and poor bioavailability have limited therapeutic use.Thus,different dosage forms of resveratrol have been explored[85,86].

Polysaccharides.Natural polysaccharides are emerging as a new class of anti-tumor agents due to their potent immunomodulation,antioxidant,anti-tumor,and anti-aging activities.Multiple natural polysaccharides have been proven with anti-tumor activities.Several review summarized the anti-tumor effects of polysaccharides,such as mushroom polysaccharides[87],polysaccharides of aloe vera[88],glucomannan from Konjac root [89],polysaccharides ofCordyceps militaris[90].Bamboo shaving polysaccharides are used as one of the bioactive polysaccharides and have potent anti-gastric cancer effects in vivo and the murine gastric cancer syngeneic model by inducing tumor cell apoptosis and remodeling the tumor microenvironment [91].Polysaccharides from theTaxus cuspidatabranches and leaves have demonstrated a functional capacity against cervical cancer[92].Liu C et al.found that the therapeutic potential forAstragaluspolysaccharides in breast cancer treatment could be through interventions with CCNB1,CDC6,and P53 via network pharmacology methods [93].Ecklonia kuromepolysaccharides are one of the marine polysaccharides,especially HW-EP5,and have great potential as a natural medicine for the treatment of breast cancer[94].Fucoidan is another marine-origin sulfated polysaccharide,and fucoidan has inhibited breast tumor growth by suppressing new blood vessel formation in vivo[95].

Saponins.Saponins are found in multiple plants and display a wide range of biological and pharmacological activities.The anti-tumor effects of saponins have been proven by their cytotoxic,cytostatic,proapoptotic,and anti-invasive effects in many cellular models.Ginseng Radix et Rhizomahas been widely used for centuries to treat various diseases such as infectious diseases [96],cancer [97],and cardiopulmonary diseases[98].There are more than 50 different ginsenosides identified by chromatography,and among them,ginsenoside Rg3,ginsenoside Rh2,and compound K are the primary bioactive compounds for cancer prevention and treatment.A review of the underlying anti-tumor mechanisms of ginsenoside Rg3,ginsenoside Rh2,and compound K [5].Chinese patent drug Shenyi capsule,composed of ginsenoside Rg3,is an important auxiliary anticancer drug in China.A meta-analysis and systematic review have provided evidence that ginsenoside Rg3 when combined with chemotherapy can improve clinical efficacy and alleviate the treatment-induced side effects for digestive system cancer [99].Koczurkiewicz P.et al.reviewed the synergetic anti-tumor mechanisms of saponins and chemotherapy with a particular focus on modulation of the cell signaling pathways associated with the promotion and progression of cancer cell proliferation,apoptosis,and metastasis [100].Panax notoginseng saponin is the major active components of

Notoginseng Radix et Rhizoma.In addition to the strong activity of cardiovascular diseases,Panax notoginseng saponins also have anti-tumor activities[101].

Alkaloids.Alkaloids are important chemical compounds that serve as an important group of anti-tumor drug discovery and vinblastine,vinorelbine,vincristine,and vindesine have already been successfully developed and used as anticancer drugs.Many other alkaloids have shown strong effects as inhibitors of cancer,such as berberine [102,103],tetrandrine [104],matrine (fromSophora flavescens Ait.) and sinomenine (fromSinomenium acutum) [105,106].The anti-tumor effects of alkaloids may be attributed to multiple mechanisms of action.Masoud Alasvand has described the effects of several alkaloids in tumor angiogenesis suppression through several mechanisms [107].Koji Wada evaluated the cytotoxic effects of the natural diterpenoid alkaloids and the semi-synthetic alkaloid derivatives against several human tumor cells and found that C19-diterpenoid(lipojesaconitine,delcosine,and delpheline derivatives)and C20-diterpenoid (kobusine and pseudokobusine derivatives) alkaloids exhibited significant cytotoxic activity[108].

Chinese formula

TCM formulas have been applied in treating various complex diseases as a principle for auxiliary drugs for more than 2,500 years.In general,the TCM formula is composed of at least two herbs or minerals under the guidance of TCM theory.In 2019,many studies focused on the efficacy,safety,and molecular mechanisms using Chinese formulas for the treatment of tumors.Among these studies,breast cancer,lung cancer,colorectal cancer,and hepatocellular carcinoma were the predominant tumor types studied (Figure5).Compared with modern medicine,TCM formulas have advantages in the treatment of precancerous lesions.Some classical prescriptions(such as Sijunzi decoction and Wumei Pill) and empirical formulas (such as Xiaopi formula) were studied in depth.The adjuvant therapy effects of several TCM formulas (such as Qingyihuaji formula and Gegen Qinlian decoction)were also included in this part.

Figure5 The top ten keywords used in traditional Chinese medicine formulas for tumor study.We searched in PubMed using the keywords traditional Chinese medicine formulas AND cancer OR tumor from 2019/01/01 to 2019/12/31 was used to analyze the keyword contributions.

TCM formula has exhibited efficacy for the treatment of precancerous lesions and thus can be used as a chemopreventive agent in the clinic.Empirical formula Weipiling wais based on an improved version of Sijunzi decoction and consisted of eight Chinese medicinal herbsAstragali Radix,Pseudostellariae Radix,Atractylodismacrocephalae Rhizoma,Notoginseng Radix et Rhizoma,Curcumae Rhizoma,Hedyotis diffusaWilld andHericium erinaceus(Rull ex F.) Pers.Weipiling ameliorates gastric precancerous lesions in Atp4a-/-mice by inhibiting the expression of transporters and suppressing the aberrant activation of mTOR/HIF-1α[109].Weiqi Decoction is an empirical formula sourced from Longhua Hospital is affiliated with Shanghai University of Traditional Chinese Medicine and is comprised ofRadix Sinensis Angelicae(12 g),

Astragali Radix(12 g),Codonopsis Radix(15 g),Curcumae Rhizoma(15 g),Aurantii Fructus(15 g),Akebiae Fructus(15 g),andTaraxaciherba(30 g).Weiqi decoction attenuats chronic atrophic gastritis with precancerous lesions through regulation of the gastric mucosal blood flow disturbance and the HIF-1α signaling pathway [110].Li J et al.found that the classical prescription Yanghe Huayan Decoction exerted chemopreventive efficacy in the classical 7,12-dimethylbenz(a)anthracene model for breast cancer by targeting multiple tumorigenic pathways simultaneously[111].

In 2019,classical prescription Sijunzi decoction was also their focus of research into the treatment of cancer.This formula was first described in theTaiping Huimin Hejijufang(Benevolent Prescriptions from Taiping Pharmaceutical Bureau) about a thousand years ago and is consisted ofGinsengRadixet Rhizoma,Atractylodis Macrocephalae Rhizoma,Poria,andGlycyrrhizae Radix et Rhizoma.at a proportion of 3 : 3 : 3 : 2.The Sijunzi decoction is a commonly used formula for the treatment of digestive system diseases in the clinic.A modified Sijunzi decoction inhibited colorectal cancer liver metastasis by increasing the number of macrophages resulting in activation of the innate immune system [112].In addition to gastrointestinal tumors,researchers have also uncovered anti-lung cancer effects.Xiaowei Zhou et al.explored the effective materials used for treating lung cancer with the Sijunzi decoction and indicated that ginsenoside Ro and ginsenoside Rg1 might be active constituents of the antiproliferative effect as determined by the spectrum-effect relationships [113].Li C et al.illustrated the modulatory properties of Sijunzi decoction,which enhanced the anticancer effects of gefitinib,using metabolomics and network pharmacology analyses.Sijunzi decoction enhanced the anti-lung cancer effects of gefitinib via the following key targets ABCG2,ABCC1,ABAT,GSR,CYP1A2,ALOX5,CYP3A4,PLA2G1B,and PLA2G2A and the key metabolites 2-oxoglutarate,taurocholic acid,oxidized glutathione and linoleic acid[114].

Empirical formula Xiaopi formula was another research focus in the treatment of cancer during 2019.Xiaopi formula is a mixture of 10 herbs,includingEpimedii Folium,Cistanches Herba,Leonuri Herba,SalviaeMiltiorrhizaeRadixet Rhizoma,CurcumaeRadix,Curcumae Rhizoma,Ligustri Lucidi Fructus,Polygoni Multiflori Radix,Ostreae Concha,andTrionycis Carapaxand is a new anti-mammary hyperplasia drug approved by the State Food and Drug Administration of China in Dec 28,2018 [115].Shengqi Wang et al.uncovered the immunomodulatory mechanism of Xiaopi formula in the treatment of breast cancer,but it also shed novel insight into the tumor-associated macrophages/CXCL1 as a potential molecular target for elimination of breast cancer using stem cells [115].Moreover,this team presented a comprehensive metabolic profile of Xiaopi formula in vivo,and the bile acid synthesis pathway might be one of the key mechanisms contributing to the pharmacological function of the formula [116].In addition,they also indicated that Xiaopi formula is a potential adjuvant drug via inhibition of CXCL1/HMGB1-mediated autophagy for breast cancer treatment with good safety[117].

Network pharmacology-based research on TCM provided a new method for understanding the interaction of active ingredients used in the TCM formulas and their molecular target network [118].Wumei Pill originated from ancient Chinese famous medicial bookShanghan Zabing Lun(Treatise on Cold Damage and Miscellaneous Diseases,200-210 C.E.)and is comprised of 10 herbsMume Fructus,Angelicae Sinensis Radix,Asari Radix et Rhizoma,Radix Aconiti Lateralis Praeparata,Cortex Phellodendri,Zanthoxyli Pericarpium,Cinnamomi Ramulus,Ginseng Radix et Rhizoma,CoptidisRhizoma,andZingiberis Rhizoma.A total of 80 active ingredients and 77 targets of the Wumei Pill were picked out.Moreover,17 hub nodes of the Wumei Pill(PTGS2,BCL2,TP53,IL6,MAPK1,EGFR,EGF,CASP3,JUN,MAPK8,MMP9,VEGFA,TNF,MYC,AKT1,FOS,and TGFB1)were recognized as potential treatment targets of the pancreatic neoplasms by utilizing the network pharmacology method[119].However,this study lacks further experimental validation.Another study explored the molecular mechanisms of empirical formula Liuju formula,containing leaves ofSalix matsudanaKoidz.,Chrysanthemum indicumL.,andHedyotis diffusaWilld,for the treatment of lung cancer.In the clinical,Chinese patent drugs compound Liuju tablets and compound Liuju granules are used to treat pulmonary tuberculosis.Xing Su et al.found that multicomponent drugs presented a synergistic effect via the regulation of inflammatory signaling pathways,invasion pathways,proliferation,and the apoptosis pathway through network analysis.Furthermore,they indicated that Liuju formula exuded a killing effect on non-small-cell lung cancer tumor cells and a synergistic effect on the inhibition of the secretion of the correlative inflammatory mediators,including TNF-α and IL-1β[120].

In addition,big data mining analysis of the TCM formulas for a specific disease was also used to explore the compatible principle and action of mechanisms [121].While dig data mining analysis is a high-efficiency method to integrate massive prescriptions and help us obtain the key medicines or drug pairs,which provides further study directions.For example,Ying Chen et al found the core Chinese medicines for the prevention and treatment of cervical cancer were herbs primarily with effects of clearing heat-toxin and removing dampness (some pathological products in TCM theory) by analyzing formulas based on the TCM inheritance support system[122].

In most cases,TCM is taken as adjuvant therapy for cancer.In the clinic,TCM formulas are often used to increase efficiency and decrease the toxicity of conventional anti-tumor therapy.For example,using TCM significantly decreases the incidence of congestive heart failure in patients with breast cancer who received conventional chemotherapy with or without radiotherapy [123].Qingyihuaji formula(QYHJ) is a novel Chinese patent medicine produced by professor Luming Liu (Department of Integrative Oncology,Fudan University Shanghai Cancer Center,China).QYHJ is comprised of five traditional Chinese herbs,Scutellariae barbatae Herba,Herba Hedyotdis,Rhizoma Arisaematis,Herba seu Radix Gynostemmatis pentaphylli,andAmomi Rotundus Fructus.QYHJ can effectively enhance the anti-pancreatic tumor activity of gemcitabine,which may be through inhibiting pancreatic cancer stem cell differentiation by the lncRNA AB209630/miR-373/EphB2-NANOG signaling pathway [124].In addition to increasing the efficiency of chemotherapy,TCM formulas also have a synergistic effect on immunotherapy.The combination therapy of classical prescription Gegen Qinlian decoction (GQD) and anti-mouse PD-1 significantly increases the proportion of CD8+T cells in the peripheral blood and tumor tissues,increases IFN-γ expression,and IL-2 levels,and downregulates the PD-1 level,which can be a novel therapeutic strategy for colorectal cancer patients with microsatellite stable tumors [125].In addition,GOD extract ameliorates CPT-11 induced gut toxicity in mice and improved CPT-11 efficacy in colorectal cancer treatment[126].

It should also be noted that some formula might affect the efficiency of conventional chemotherapy when they are used in combination.One study found that classical prescription Baihe Zhimu decoction consisted ofLilium browniiandAnemarrhena Rhizomamight attenuate the effectiveness of tamoxifen in the treatment of breast cancer in mice by influencing the CYP450 enzymes[127].

Traditional medicine in other countries

The type of traditional medicine varies widely,and the choice of traditional medicine depends on the cultural setting and availability of interventions and drugs(Figure1).In addition to TCM,many other traditional medicines also have made important contributions to the treatment of cancer(Figure6).

Figure6 The mainstream types of traditional medicine used worldwide.

Thai traditional medicine

Thai traditional medicine (TTM) has been used widely in cancer management in Thailand.TTM is considered a holistic medical system,focusing on maintaining the balance of the body,particularly,the four fundamental elements which are earth (the structural organs and is about the physical makeup and building blocks of the body),water (all liquids,phlegm and semi-solids flowing and being absorbed by the body),wind (the energy that controls movement in the activities and functions of the body) and fire (vital heat energy that warms and heat-up the body).TTM has proven benefits in the relief of symptoms and improvement in the quality of life for cancer patients [128].The integration of TTM and Western medicine has been ongoing by the Ministry of Public Health in Thailand and TTM practitioners,but several problems must still be overcome before the final implementation of the integration of TTM,and Western medicine[129].

Herbal or traditional medicine use is popular in the Thai worker population for the treatment of chronic diseases and the top eight herbs for cancer patients are

Ganoderma lucidum,Panax ginsengC.A.Mey.,Cinnamomum spp.,Curcuma longaL.,Carthamus tinctoriusLinn.,Mixed botanical preparations,KaempferiaparvifloraWallich.ex Baker.,Andropraphis paniculata(Burm.f.) Wall.Ex Nees[130].In the past year,several herbs in TTM were proven to elicit anti-tumor potential,includingAcanthus ebracteatusVahl.(anti-epidermoid cancer)[131],S.rugata(chemopreventive properties) [132],T.laurifolia(chemopreventive properties) [132],Perilla frutescens (against oxidative stress) [133],Champi Sirindhorn (Magnolia sirindhorniae) (inhibition of leukemic cell proliferation) [134],Baliospermum montanum (cytotoxic activities) [135],andMesua ferreaL.(cytotoxicity)[136].

Traditional medicine in Sri Lanka

Sri Lanka has a rich history of the practice of traditional medicine dating back many centuries.This practice is a mixture of the Sri Lankan indigenous medical system “deshiya chikitsa” ayurveda and siddha systems,introduced by India,and the unani system that originated in Greece and was introduced by the Arabs to Sri Lanka[137].The Sri Lankan herbal preparations or traditional medicine formulas used against cancer typically contain extracts from more than one plant species[138].

In 2019,several plants,or ingredients have been reported to have anticancer properties.Anchala I.Kuruppu et al.summarized ten terrestrial plant species commonly found in an anticancer herbal preparation from the traditional medicine system of Sri Lanka,includingZingiber officinale,Cucurma longa,Hemidesmus indicus,Munronia pinnata,Smilax zeylanica,Tinospora cordifolia,Adenanthera pavonina,Thespesia populnea,Phyllanthus emblica,Boerhaviadiffusa[139].Another review also focused on Sri Lankan plants that possessed anticancer properties,from marine organisms,microbial organisms to terrestrial plants [138].Vernonia zeylanicaalso has been used in Sri Lankan traditional medicine for the treatment of various diseases and conditions.Vernolactone,isolated fromV.zeylanica,exerts antiproliferative effects,induces apoptosis,and autophagy,and decreases NTERA-2 cell migration in a dose- and time-dependent manner with a very small antioxidant property[140].

Traditional African medicine

Due to socio-economic reasons,many African pe o?ple have resorted to traditional medicine using natural products to treat diseases,including cancer [141].One survey was conducted on the anticancer potential of plants used in the Arabian and Islamic world and listed more than ten plants used for the treatment of cancer by people in this region[142].

One study explored the potential action of the mechanisms of North African plants(about 1,000 plant source) and their chemical constituents (6,844) using the network pharmacology method.This study found that the main constituents were luteolin,alternariol,apigenin,aloe-emodin,and myricetin.Many of the main constituents were flavonoids and AKT1,TP53,CASP3,and EGFR were the main hit targets.Plant-constituent-target network revealed thatEuphorbia spp.,Hyphaene thebaica,Artemisia herba-alba,bee propolis,andMarrubium vulgarepossessed the largest number of constituent-target interactions which might imply that these plants contained more active constituents than what was utilized during the cancer treatment[141].

For centuries,Moringa oleifera Lam.has been widely used in African traditional medicine in the form of aqueous infusions,to promote health and cure diseases [143].Moringa oleifera Lam aqueous extracts appear to be able to differentially regulate proliferation and apoptosis in healthy cells and cancer cells,and this ability can be associated with the microRNA present in the extracts [144].Another study indicated that the crude extract and several compounds from the bark ofFagara tessmanniiEngl.(Rutaceae),an African medicinal plant used in Cameroonian traditional medicine,exhibited cytotoxicity toward a panel of drug-sensitive and drug-resistant cancer cell lines[145].

Traditional Korean medicine

Similarly to TCM,traditional Korean medical practice is also based on dialectic,individual diagnosis,and treatment according to the patient’s personal condition[146].Meanwhile,many medicines are used both in Chinese and Korean traditional medicine,such asCitrus unshiu Marcow.Fruits,asiasari radix,and Prunus mume.Citrus unshiu Marcow.Fruitscalls“Jinpi” in Korea and “Chenpi” in China and the ethanol extracts ofCitrus unshiu Marcow.Fruitpeel has potential as a prevention against melanoma in vitro and in vivo [147].The ethanol extract of asiasari radix preferentially induces apoptosis in the melanoma cells by the reactive oxygen species-dependent differential regulation of p53 level [148].A review summarized the anticancer properties of the Prunus mume extracts,including melanoma cells,non-small cell lung cancer cells,pancreatic cancer cells,breast cancer cells,and liver cancer cells[149].

Several herbs or formulas have been indicated with the potential to reduce the side effects of the chemotherapy drugs.For example,the neuroprotective effects of an aqueous extract ofForsythia suspensefruits on oxaliplatin-induced peripheral neuropathy are confirmed [150].In addition,Hwi-Joong Kang et al.found Yukgunja-tang,also known as Rikkunshito in Japan and Liujunzi decoction in China,was effective and safe for treating patients with cancer-related anorexia in Korea [151].Taeeumjowi-tang is a traditional Korean medicine that is usually prescribed for a particular type of person to regulate stomach-related symptoms.Taeeumjowi decoction inhibits cell growth in p53-mutant prostate cancer cells DU145,as indicated by blocking lipogenesis and induction in G1/S cell cycle arrest.[152].

Traditional Japanese medicine

Japan has its own traditional medicine called Kampo medicine,including herbal medicine,acupuncture,and moxibustion.The Japanese government granted more research projects on Kampo medicine in the 2000s,and it increased sharply in the 2010s [153],which indicated that the Japanese government and researchers paid more and more attention to the development of the Kampo medicine.

Similar to traditional Korean medicine,many medicines or formulas are used both in TCM and Kampo medicine,such asPrunus mume,Sophora flavescens,and Juzentaihoto.A review summarized the anticancer properties ofPrunus mumeextracts(Chineseplum,Japanese apricot),notably for gastrointestinal tumors,and P.mume extracts also were used to prevent or to treat mucositis and other gastrointestinal damage induced by anticancer drugs[149].Kurarinone,an extract from the Sophora flavescens root,exhibits potent cytostatic effects on the cancer cells by modulation of the PERK-ATF4 pathway [154].Juzentaihoto (Shiquan Dabu decoction in Chinese and Sipjeondaebo decoction in Korean)is a traditional Japanese herbal formula,comprised of 10 herbs.In Japan,it has been traditionally used as an additional therapy in patients with anemia,fatigue,anorexia,scaly skin,and dry mouth.Shun Takaku et al.indicated that in the absence of NKT cells,Juzentaihoto augmented anti-tumor immunity by the CD8+T cells[155].

In addition,there are many local herbs and formulas in Japan.Xanthoangelol,a prenylated chalcone isolated from the Japanese herb Angelica keiskei Koidzumi,which exerts anti-metastatic properties against hepatocellular carcinoma through inducing autophagy which is mediated by the activation of the AMPK/mTOR signaling pathway [156].Yokukansan is a Japanese herbal medicine consisting of 7 main galenicals [157],and yokukansan may exert an anti-tumor effect by reversing changes in the fecal microbiota and miRNAs circulating in the blood serum and hypothalamus [158].Moreover,several compounds found in yokukansan have direct and additive anti-tumor effects[158].

In 2019,more studies focused on cancer-related or therapy-related complications in Kampo medicine,such as hiccups,pain,and cancer-related anorexia.Shitei extract is an effective and safe therapeutic drug for the treatment of hiccups,especially for patients after chemotherapy [159].Yokukansa can alleviate cancer pain via suppressing MMP-9 expression in the bone metastasis mice model [160].Rikkunshito contains several mixed raw herbs,is a popular orexigenic Japanese traditional medicine that is prescribed in Japan to treat various gastrointestinal tract disorders.Rikkunshito can mitigate chemotherapy-induced anorexia and ameliorate plasma acylated ghrelin levels during the delayed phase of cisplatin-based chemotherapy in lung cancer patients[161].In addition,Rikkunshito also can improve cisplatin-induced,delayed-onset anorexia and increased plasma acylated ghrelin levels among patients with esophageal cancer who undergo highly emetogenic chemotherapy [162].Ninjin-yoeito,another Japanese kampo medicine,is comprised of twelve herbs and has been used to treat anorexia.Ninjin-yoeito directly targets both ghrelin-responsive and unresponsive neuropeptide Y neurons in the arcuate nucleus and preserves food intake and body weight in cisplatin-treated anorectic mice [163],which may provide a strong mechanistic basis for ninjin-yoeito use when treating anorectic conditions associated with cancer,depression,heart failure,sarcopenia,frailty,and aging.

Conclusion and perspective

Traditional medicine is an indispensable part of world medicine for disease therapy,including cancer.In this review,we summarized the research progress of several traditional medicines used as a cancer therapy in 2019.Traditional medicines in different countries exhibit some common characteristics,such as the use of local herbal medicines and formulas to treat disease.Meanwhile,different traditional medicines elicited unique features.

There were thousands of papers in the field of traditional medicine used for cancer therapy published in 2019.Most of the papers were basic research studies,and only a few papers were clinical studies.Likely because,the characteristics of the multicomponent and multi-targeted herbal medicines and formulas make them difficult to study and illuminate.With the development of network analysis for ingredients,targets and diseases,a great deal of the herbs and formulas are interpreted to some degree.However,most of the studies require further laboratory and clinical verification to provide evidence for their appropriate clinical use.It is also important to note that the evaluation of the efficacy and safety of traditional medicines should take the compatibility of different medicines into account rather than break them down into single active ingredients.Meanwhile,the use of traditional medicines is individualized based on the condition of the different patients in TCM theory.Current studies rarely take this into account.In addition,we also should pay attention to the drug toxicity of traditional medicines when used alone or combined with modern medicines.