journal of applied biomedicine 12 (2014) 49–61

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Review Article scaber Linn.: A review on its ethnomedical, phytochemical and pharmacological profile

Sachin M. Hiradeve *, Vinod D. Rangari

School of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya, Koni, Bilaspur 495009, Chhattisgarh, article info abstract

Article history: Linn., family , is a small herb found in Neotropics, Europe, Received 21 October 2013 , and . The parts of this herb have been used traditionally for the Received in revised form treatment of a number of diseases in many countries. Sesquiterpene lactones, triterpenoids, 21 December 2013 steroids, flavonoids and essential oil constituents have been reported from various parts of Accepted 24 January 2014 the plant. The plant has been extensively screened for anticancer activity. Sesquiterpene Available online 5 February 2014 lactones such as deoxyelephantopin, isodeoxyelephantopin, scabertopin, and isoscaberto- pin have been found to be prominent anticancer constituents. Many other biological fl Keywords: activities such as antimicrobial, hepatoprotective, antioxidant, antidiabetic, anti-in amma- Elephantopus scaber tory, analgesic, antiasthamatic, antiplatelet, and wound healing have been reported in various research papers. The present review has been envisaged with an intension to fi Sesquiterpene lactones provide scienti c information about the ethnomedical, phytochemical and pharmacological fi Deoxyelephantopin pro le of E. scaber. # Antitumor 2014 Faculty of Health and Social Studies, University of South Bohemia in Ceske Budejovice. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

30–60 cm high. Stems are forked and stiff, while leaves are Introduction mostly in basal rosette and oblong-ovate to oblong-lance like, 10–25 cm in length and often very much notched on the The genus Elephantopus was established in Asteraceae family margins. Purple flowers are 8–10 mm long and each flower by Linnaeus in 1753. It is a genus of about 32 species centered head comprises about 4 flowers. Flowering heads are borne in in the Neotropics (extending from southern through clusters at the end of the branches and are usually enclosed by Central America and Northern South America to Southern 3 leaf-like bracts which are ovate to oblong-ovate, 1–1.5 cm ), Europe, Asia (India, Nepal, Pakistan, Sri Lanka, , long, and heart-shaped at the base. The flowering heads are Taiwan, Hong Kong, Japan, Malaysia, Indonesia, Vietnam, many, crowded in each cluster, while the fruits are achenes, Philippines, Thailand and Myanmar), Australia and Africa ribbed and pappus, from 4 to 6 mm long with rigid ristles (Kurokawa and Nakanishi, 1970; Kiritikar and Basu, 1991; (Kiritikar and Basu, 1991). Taylor et al., 1995; Hui and But, 1998; Singh et al., 2005; Than Among the 32 species, only one species, namely, E. scaber,is et al., 2005; Wright et al., 2007). The lectotype species of known to grow in India (Geetha et al., 2012). The plant has been Elephantopus genus, i.e., Elephantopus scaber Linn. family abundantly found throughout India, for example Western Asteraceae, is a common wild weed that forms undergrowth Ghats, and widely distributed in the forest of Achanakmar, in shady places. It is a rather coarse, rigid, erect, hairy herb, Chhattisgarh State. It is popularly known as Prickly leaved

* Corresponding author. Tel.: +91 8871801377; fax: +91 7752260148. E-mail addresses: [email protected], [email protected] (S.M. Hiradeve). 1214-021X/$ – see front matter # 2014 Faculty of Health and Social Studies, University of South Bohemia in Ceske Budejovice. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved. http://dx.doi.org/10.1016/j.jab.2014.01.008 50 journal of applied biomedicine 12 (2014) 49–61

elephant foot or elephant's foot (English). In India it is known 1998). In Nigeria, hot water extract of leaves is used to cure by a variety of local names such as Gojivha or Hastipadi arthritis (Hammer and Johns, 1993; Hui and But, 1998). In (Sanskrit) and Gobhi (Hindi) (Kiritikar and Basu, 1991). In China Mauritius two pieces of roots and six leaves in 1 l of water the plant is called as Didancao (Hui and But, 1998). provide treatment for diarrhea and urinary problems and root In folk medicinal practices, various parts of the plant and paste, for pimples (Gurib-Fakim et al., 1993). even the whole plant of E. scaber have been used in many countries for the treatment of a number of diseases. Detailed ethnomedical review of E. scaber is as follows. Phytochemical review

Several studies on various plant species of genus Elephantopus Ethnomedical history report the presence of sesquiterpene lactones (Kupchan et al., 1969; Kurokawa and Nakanishi, 1970; Desilva et al., 1982; E. scaber has been widely used in traditional medicine for Zhang et al., 1986; Hayashi et al., 1987; Jakupovic et al., 1987; various diseases in many countries of the world. Decoction of But et al., 1997; Than et al., 2005; Ichikawa et al., 2006; Tabopda whole plant or roots of E. scaber is most commonly used in et al., 2008; Liang et al., 2008; Su et al., 2009, 2011; Huang et al., countries such as India, China, Vietnam, Hong Kong, 2010; Chang et al., 2011; Ho et al., 2011; Geetha et al., 2012; Lee Philippines, Thailand, , Nepal and Brazil as an and Shyur, 2012; Mei et al., 2012). Sesquiterpene lactones are a anti-inflammatory, antipyretic, diuretic, anticough agent, class of naturally occurring plant terpenoids that represent a antibiotics, emollient and tonic (Kiritikar and Basu, 1991; Poli diverse and unique category of natural products and charac- et al., 1992; Rasoanaivo et al., 1992; Hammer and Johns, 1993; teristic constituents of family Asteraceae (Chaturvedi, 2011). Hui and But, 1998; Chuakul et al., 2006; Inta et al., 2008; Udayan Being a rich source of sesquiterpene lactones, there have been et al., 2008). renewed interests of researchers all over the world in the In India it is used in cases of cardiovascular diseases, phytochemistry of E. scaber. bronchitis and smallpox (Kiritikar and Basu, 1991). Root Apart from sesquiterpene lactones, other phytochemical powder mixed with boiling water is given internally to cure constituents of E. scaber include triterpenoids, steroids and burning sensation and gonorrhea (Sahu, 1984; Ayyanar and their glycosides. It also contains flavonoids, phenolic com- Ignacimuthu, 2005). Roots are used in heart and liver trouble, pounds, long chain hydrocarbons and essential oils (Table 1). and hot water extract of root is given in filariasis and diarrhea Detailed phytochemical review of E. scaber is as follows. (Hammer and Johns, 1993). The fresh root of the plant is employed for treating spermatorrhea, leucorrhoea, ametror- Sesquiterpene lactones rhagia, menstrual complaints, menorrhagia and dysmenor- rhea (Behera and Misra, 2005). The paste of roots is tied Sesquiterpene lactones present in E. scaber includes deoxye- around the ear to cure headache (Rajakumar and Shivanna, lephantopin, isodeoxyelephantopin, scabertopin, isoscaberto- 2010) and the paste of leaves has been used to treat pin, elescaberin, 17,19-dihydrodeoxyelephantopin, iso-17,19- menorrhagia (Pattanaik et al., 2008). The plant paste is dihydrodeoxyelephantopin, 11,13-dihydrodeoxy-elephanto- applied externally in rheumatism and on patients suffering pin and scabertopinol. The structure of these sesquiterpene from tetanus (Sahu, 1984). The entire plant or its decoction is lactones is given in Fig. 1. used in India and Malaysia for quick delivery and expulsion of Deoxyelephantopin (C19H20O6)isoneofthemainsesqui- placenta, and external application of emulsion of dried bark terpene lactone isolated from the aqueous, ethanol, chloro- is used for wound healing (Hammer and Johns, 1993; Hui and form, acetone extract of whole plant and ethanolic extract of But, 1998; Kumar et al., 2007). In Ayurveda, herbal combina- root of E. scaber. The aqueous extract has been partitioned tions containing E. scaber along with other herbs were used with ethyl acetate and then deoxyelephantopin isolated from for treatment of major and minor neoplasms (Balachandran the ethyl acetate extract by silica gel column containing and Govindarajan, 2005). Besides E. scaber roots are used CHCl3/EtOAc gradient elution (Huang et al., 2010). From externally as anti-venom, as antiseptic for cuts and wounds chloroform extract, deoxyelephantopin has been isolated and on lesions for chicken pox and widely used for the by silica gel column using hexane/EtOAc gradient elution. treatment of dysentery, diarrhea, stomach troubles and Deoxyelephantopin (mp 198–200 8C) has been crystallized hemoptysis in tuberculosis (Bhattarai, 1989; Hammer and from petroleum ether–EtOAc mixture as colorless needles. Johns, 1993; Taylor et al., 1995). Its root juice has been The structure of deoxyelephantopin has been elucidated by consumed to relieve heart and liver troubles, leaf juice is used using spectral data such as IR, 1HNMR,13CNMRandMS for healing wounds, while its fresh roots are chewed to treat (Kurokawa and Nakanishi, 1970; But et al., 1997; Than et al., cough, cold and headache (Bhattarai, 1989; Bhandary et al., 2005; Xu et al., 2006; Liang et al., 2008; Su et al., 2009; Geetha 1995; Taylor et al., 1995). et al., 2012).

Apart from these common uses, it is used for removing Isodeoxyelephantopin (C19H20O6) has been reported as bladder stone in Brazil (Poli et al., 1992). In Taiwan, oral another important sesquiterpene lactone isolated from chlo- administration of whole plant decoction is used to treat roform (Geetha et al., 2012), ethanol extract (Liang et al., 2008) hepatitis (Hammer and Johns, 1993). In Malaysia, decoction of of whole plant and ethanol extract of root of E. scaber (Su et al., whole plant with red beans has been used to treat flatulence 2009). The colorless needle of isodeoxyelephantopin (mp 151– (Ong and Nordiana, 1999). In Pakistan, it is used for the 153 8C) has been crystallized from petroleum ether–EtOAc treatment of round worms and venereal diseases (Hui and But, mixture (Geetha et al., 2012). journal of applied biomedicine 12 (2014) 49–61 51

Table 1 – Phytochemical composition of various extracts of E. scaber. Plant parts Extract Isolated constituents References

Whole plant Light petroleum Epifriedelinol, lupeol, stigmasterol, and a mixture of triacontan-l-o1 and Sim and Lee (1969) ether (60–80 8C) dotriacontan-l-ol Essential oil Cyclosativene, copaene, isopropyl dimethyl hexahydronaphthalene, Wang et al. (2004) trimethyl dimethylenedecahydronaphthalene, zingiberene, b-caryophyllene, caryophyllene, dimethyl-6-(4-methyl-3-pentenyl)-2-norpinene, b- sesquiphellandrene, isocaryophyllene, a-santalol, ledol, a-bisabolol, caryophyllene b-bisabolol, isopropyl dimethyl tetrahydronaphthalenol, cadinol, oxide, hexahydrofarnesyl acetone Chloroform Lupeol acetate, deoxyelephantopin and isodeoxyelephantopin Kurokawa and Nakanishi (1970), Ichikawa et al. (2006), and Geetha et al. (2012) Acetone Deoxyelephantopin, iso-17,19-dihydrodeoxyelephantopin, 6-[1-(10,13- Daisy et al. (2008, 2009a) dimethyl-4,5,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a] and Than et al. (2005) phenanthren-17-yl) ethyl]-3-methyl-3,6 dihydro-2H-2 pyranone and 28Nor-22 (R) witha 2,6,23-trienolide Methanol Lupeol, stigmasterol, 11,13-dihydrodeoxy-elephantopin Desilva et al. (1982) Ethanol Elescaberin, isodeoxyelephantopin, deoxyelephantopin, scabertopin, 17,19- Liang et al. (2008), dihydrodeoxyelephantopin, ethyl hexadecanoate, ethyl-9,12- Sim and Lee (1969) octadecadienoate, ethyl-(Z)-9-octadecenoate, ethyl octadecanoate, lupeol, and Than et al. (2005) stigmasterol, stigmasterol glucoside, potassium chloride and phenolic compounds Aqueous Deoxyelephantopin Huang et al. (2010)

Aerial part Methanol Scabertopinol, trans-caffeic acid, methyl 3,4-dicaffeoylquinate, luteolin-41-O- Chang et al. (2011) b-D glucoside, trans-p-coumaric acid, indole-3-carbaldehyde, methyl trans- caffeate, luteolin-7-O-glucuronide 600-methyl ester, and luteolin Leaves Dichloromethane Hexadecanoic acid, phytol, octadecadienoic acid, n-tetradecane, n- Wang et al. (2005) pentadecane, n-hexadecane, n-heptadecane, n-octadecane and tetramethylhexadecenol Root Ethanol Deoxyelephantopin, isodeoxyelephantopin, scabertopin, tricin, luteolin, Su et al. (2009) lupeol acetate, lupeol, betulinic acid, epifriedelanol and ursolic acid

1 Scabertopin (C20H22O6) was reported from the ethanolic established and from the spectral data analysis by IR, H NMR extract of whole plant as well as root, while isoscabertopin and mass fragmentation pattern studies (Desilva et al., 1982).

(C20H22O6) was reported only from the ethanolic extract of Chang et al. (2011) reported the isolation of a new whole plant of E. scaber. The structure and stereochemistry of sesquiterpenoid, scabertopinol (C15H16O6), from the metha- scabertopin have been established by single crystal X-ray nolic extract of aerial part of E. scaber. The structure of colorless analysis and supporting spectral data (But et al., 1997; Xu et al., prisms of scabertopinol (mp 246–248 8C) has been established 2006; Su et al., 2009). on the basis of chemical evidence and spectroscopic method. A new elemanolide sesquiterpene lactone, elescaberin

(C20H24O7), has been reported from the ethanolic extract of Hydrocarbon compounds E. scaber. The structure of elescaberin has been established by careful analyses of the IR, 1HNMR, 13C NMR, MS, HMQC, HMBC, Dried leaf samples of E. scaber with dichloromethane yielded and NOESY spectra (Liang et al., 2008). 24 compounds, of which 20 compounds were identified by – Iso-17,19-dihydrodeoxyelephantopin (C19H22O6, mp 183 using GC/MS. The major compounds include hexadecanoic 185 8C) was obtained from the acetone extract of whole plant of acid (8.19–39.22%); octadecadienoic acid (trace – 29.22%); five E. scaber by using silica gel column chromatography, prepara- alkane homologues, i.e., n-tetradecane (1.19–5.26%), n-penta- – – tive TLC and preparative HPLC (CH3CN/H2O, 40:60) method. decane (3.22 12.05%), n-hexadecane (2.38 16.26%), n-hepta- Spectral data from the IR, 1H NMR, 13C NMR and ESI-MS decane (2.48–15.32%), and n-octadecane (1.39–9.59%), and confirmed the structure of the compound. 17,19-Dihydrodeox- tetramethylhexadecenol (2.06–4.31%). Hierarchical cluster fi yelephantopin (C19H22O6) was isolated from the ethanolic analysis classi ed the leaf oils into two groups, one rich in extract of E. scaber. The structure and stereochemistry of 17,19- hexadecanoic acid and octadecadienoic acid and the other rich dihydrodeoxyelephantopin have been established by single in the five alkane homologues (Wang et al., 2005). crystal X-ray analysis and supporting spectral data (Than et al., 2005). Essential oil A new germacranolide dilactone, 11,13-dihydrodeoxyele- phantopin (C19H22O6), was isolated from the methanolic Steam distillation of whole plant of E. scaber using a Clevenger- extract of the whole plant of E. scaber. The structure of white type apparatus gave a clear, yellowish essential oil in 0.05% needles of 11,13-dihydrodeoxyelephantopin (mp 234 8C) was yield (v/w). GC–MS studies of the essential oil identified a total 52 journal of applied biomedicine 12 (2014) 49–61 [(Fig._1)TD$IG]

O O O

O CH O 3 CH3 O O CH2 H3C CH2 H3C O O CH2 CH2 O O

Deoxyelephantopin Isodeoxyelephantopin

O O O O H3C H3C O O CH3 CH3 O O CH3 CH3 H3C H3C O O CH2 CH2 O O

Scabertopin Isoscabertopin

O O O O CH3 H2C O OH H3C O CH3 H C HO CH3 3 O HO OH O O Elescaberin Scabertropinol O O O O

H2C O O CH3 CH 3 O H C O CH 3 H3C 3 O O CH3 CH2 O O 11,13-dihydrodeoxyelephantopin 17,19-dihydrodeoxyelephantopin

O O

O CH3 O CH3 H3C O CH2 O

Iso-17,19-dihydrodeoxyelephantopin

Fig. 1 – Sequiterpene lactones isolated from the whole plant of E. scaber having potential antitumor activity. journal of applied biomedicine 12 (2014) 49–61 53 [(Fig._2)TD$IG]

H C of 21 compounds. The essential oil constituents identified 3 CH3 CH include cyclosativene, copaene, isopropyl dimethyl hexahydro- 3 O O naphthalene, trimethyl dimethylenedecahydronaphthalene, CH3 zingiberene, b-caryophyllene, caryophyllene, dimethyl-6-(4- methyl-3-pentenyl)-2-norpinene,b-sesquiphellandrene,isocar- yophyllene, a-santalol, ledol, a-bisabolol, caryophyllene oxide, 6-[1-(10,13-dimethyl-4, 5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-1H-cyclopenta[α] b-bisabolol, isopropyl dimethyl tetrahydronaphthalenol, cadi- phenanthren-17-yl) ethyl]-3-methyl-3,6 dihydro-2H-2 pyranone nol, hexahydrofarnesyl acetone, hexadecanoic acid, phytol and CH3 octadecadienoic acid. Among these compounds the major H3C constituents are hexadecanoic acid (42.3%), isopropyl dimethyl O O CH tetrahydronaphthalenol (14.1%), b-sesquiphellandrene (8.3%), 3 octadecadienoic acid (5.5%), and phytol (5.2%) (Wang et al., 2004). CH3

Steroids and other constituents 28Nor-22(R) Witha 2,6,23-trienolide Lupeol and stigmasterol have been reported from the light petroleum ether, methanol and ethanol extract of the whole Fig. 2 – Structure of novel steroids isolated from the acetone plant of E. scaber (Sim and Lee, 1969; Desilva et al., 1982; Than extract of E. scaber. et al., 2005). Light petroleum ether extract also yielded epifriedelinol and a mixture of triacontan-l-o1 and dotriacon- tan-l-ol. Petroleum extract separated into an acidic fraction and a neutral fraction. The acidic fraction failed to give any crystalline compound on chromatography on silica gel. Chro- of disease conditions. Many of these ethnomedical uses have matography of the neutral sticky residue on alumina yielded all been scientifically validated by the results of biological activity the compounds reported above. Further the structure of studies. Review of these biological activity studies is presented compounds was confirmed by melting point, optical rotation, in the following section. elemental analysis and spectral study (Sim and Lee, 1969). Ethyl hexadecanoate, ethyl-9,12-octadecadienoate, ethyl- Antitumor activity (Z)-9-octadecenoate, ethyl octadecanoate, stigmasterol gluco- side, potassium chloride and phenolic compounds have been It is evident from the phytochemical review of E. scaber that it isolated from the ethanolic extract of whole plant of E. scaber contains novel sesquiterpene lactone compounds. Many (Sim and Lee, 1969; Than et al., 2005). Su et al. (2009) reported researchers have studied and reported the biological activity the isolation of two flavonoids, tricin and luteolin; and five of these compounds. However, antitumor activity of the triterpenoids, lupeol acetate, lupeol, betulinic acid, epifriede- sesquiterpene lactones has been subjected to both in vitro lanol and ursolic acid from the ethanolic extract of root of E. and in vivo studies. A review of these studies is as follows. scaber. The structure of these compounds has been established by using NMR and MS spectral data and by its comparison with In vitro antitumor activity published data. Deoxyelephantopin and other analogs of sesquiterpenoids Chang et al. (2011) reported the isolation of eight known from E. scaber have been demonstrated in numerous laborato- compounds such as trans-caffeic acid, methyl 3,4-dicaffeoyl- ries worldwide to have broad-spectrum antitumor activity quinate, luteolin-41-O-b-D glucoside, trans-p-coumaric acid, against many tumor models. indole-3-carbaldehyde, methyl trans-caffeate, luteolin-7-O- Deoxyelephantopin exhibited strong effect on the PC-3 glucuronide 600-methyl ester, and luteolin from the methanolic (human prostate carcinoma cell), CNE (human nasopharyn- extract of aerial part of E. scaber. geal carcinoma epithelial cell) and HL-60 (human acute A novel steroidal compound {6-[1-(10,13-dimethyl- promyelocytic leukemia cell). In CNE cell it inhibited the 4,5,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a] CNE cell proliferation by arresting cell cycle in S and G2/M phenanthren-17-yl) ethyl]-3-methyl-3,6 dihydro-2H-2 pyra- phases and also triggered apoptosis in CNE cells. Dysfunction none} and withanolides {28Nor-22(R) witha 2,6,23-trienolide} of mitochondria was found to be associated with the has been isolated from the acetone extract of whole plant of E. deoxyelephantopin-induced apoptosis as evidenced by the scaber which has indicated significant antibacterial activity. loss of mitochondrial membrane potential, the translocation Based on the NMR study result, the 3D structure of the of cytochrome C, and the regulation of Bcl-2 family proteins compound was predicted using software and spectral data (Su et al., 2009, 2011). provided by the structure of steroids as depicted in Fig. 2 (Daisy Isodeoxyelephantopin mediated its effects by suppressing et al., 2008, 2009a). nuclear factor kB (NF-kB) activation and potentiated apoptosis. It inhibited activation of NF-kB by a variety of inflammatory agents and in a variety of cell lines such as KBM-5 (human Pharmacological review chronic myeloid leukemia), H1299 (lung adenocarcinoma), HL60 (human promyelocytic leukemia), A293 (human embry- Review of ethnomedical history of E. scaber clearly indicates its onic kidney carcinoma), MCF-7 (human breast adenocarcino- use in various parts of the world for the treatment of a variety ma), MM.1S (human multiple myeloma), and U266 (human 54 journal of applied biomedicine 12 (2014) 49–61

multiple myeloma cell lines) and RAW 264.7. Specifically, NF- from the E. scaber and seems to be a very promising compound kB activity was inhibited because isodeoxyelephantopin for the treatment of cancer. Hence only deoxyelephantopin suppressed IKK activation, resulting in inhibition of IkBa has been subjected to in vivo antitumor activity studies against phosphorylation and degradation. Consequently, isodeoxye- various cell lines tested in mice. lephantopin also blocked p65 phosphorylation and p65 Deoxyelephantopin significantly reduced the growth rate of nuclear translocation. Furthermore, it suppressed expression primary tumors in vivo of stably transfected HeLa cell (Xu et al., of gene products involved in cell proliferation, antiapoptosis, 2006). Against a murine mammary adenocarcinoma cell line and invasion. Suppression of NF-kB by isodeoxyelephantopin (TS/A), human breast adenocarcinoma cell line (MCF-7), enhanced the apoptosis induced by TNF and inhibited TNF- human breast skin fibroblast cell line (CCD966SK), metastatic induced cellular invasion and osteoclastogenesis (Ichikawa human breast cancer cell line (MDA-MB-231) and noncancer- et al., 2006). ous human mammary epithelial cell line, deoxyelephantopin Against DLA tumor cells, deoxyelephantopin and isodeox- has potential as a chemopreventive agent for breast cancer yelephantopin act selectively on quiescent and PHA-stimulat- and suppresses mammary adenocarcinoma and lung metas- ed proliferating human lymphocytes and inhibit tritiated tasis and doubles survival time in mice by several mechanisms thymidine incorporation into cellular DNA of DLA tumor cells (Huang et al., 2010). and cause apoptosis. Therefore, the result indicated that Later Lee and Shyur (2012) observed that deoxyelephanto- deoxyelephantopin and isodeoxyelephantopin are not cyto- pin exhibits more profound suppression than paclitaxel (PTX) toxic to normal human lymphocytes and only the proliferating of lung metastasis of mammary adenocarcinoma TS/A cells in cells were affected and hence could be used in regimens for mice. Deoxyelephantopin significantly deregulates adhesion treating tumors with extensive proliferative potencies (Geetha formation in TS/A cells, probably through inhibition of m- et al., 2012). calpain activity. Epithelial growth factor (EGF)-mediated Deoxyelephantopin, isodeoxyelephantopin, scabertopin, activation of Rho GTPase Rac1 and formation of lamellipodia isoscabertopin and elescaberin have been studied against in TS/A cells were remarkably suppressed by deoxyelephan- SMMC-7721, Caco-2 and HeLa cell lines in vitro. All the above topin treatment. Further, deoxyelephantopin impaired vesic- compounds exhibited significant antitumor effect in a con- ular trafficking of EGF and induced protein carbonylation and centration-dependent manner, except isoscabertopin. The formation of centrosomal aggregates in TS/A cells. Deoxyele- effect of isoscabertopin on the growth of tested cell lines phantopin-induced reactive oxygen species were observed to was relatively weak (Xu et al., 2006; Liang et al., 2008). be the upstream stimulus for the formation of centrosomal Deoxyelephantopin, 17,19-dihydrodeoxyelephantopin and ubiquitinated protein aggregates that might subsequently iso-17,19-dihydrodeoxyelephantopin were investigated for restrict cancer cell motility. anticancer activity in vitro in a panel of 34 human tumor cell Because of sesquiterpenoids present in E. scaber, the lines. The screening comprised cell lines derived from bladder, aqueous extract of leaves of E. scaber against Dalton's central nervous system, colon, gastric, head and neck, lung, ascitic lymphoma (DAL) in swiss albino mice showed a mammary, ovarian, pancreatic, prostate, renal and uterus significant enhancement of mean survival time, and hence cancers, as well as cell lines established from melanomas and tumor cell growth was found to be inhibited (Rajkapoor et al., pleural mesothelioma. However, with regard to the tumor 2002). selectivity, some differences were found between the com- Details of anticancer activity study of sesquiterpene pounds. The melanoma-derived cell line MEXF 394NL was lactones isolated from the different extracts of E. scaber and sensitive to all the three compounds. Deoxyelephantopin crude extract against various cell lines are given in Table 2. effected pronounced activity in the mammary cancer cell line MAXF 401NL, while 17,19-dihydrodeoxyelephantopin was Antibacterial activity found to be highly effective in the renal cancer cell line RXF 944L, and iso-17,19-dihydrodeoxyelephantopin showed marked Ethnomedical review of E. scaber indicated that the plant and activity on the large cell lung cancer LXFL 529L (Than et al., 2005). itsextractarecommonlyusedasantibioticinmanycountries. The literature review clearly indicates that the sesquiter- Significant antibacterial and antifungal activity of the extract penoid lactones reported from the ethanolic and aqueous proves these ethnomedical claims. A review of antibacterial extract of E. scaber are the only constituents responsible for and antifungal activity studies has been elaborated as significant antitumor activity. The ethanolic extract of E. scaber follows. could inhibit growth and triggered time-dependent and Petroleum ether and chloroform extracts of the above dosage-dependent cell death in the MCF-7 breast cancer cell ground parts of E. scaber were investigated for its antibacterial line via a p53-dependent apoptotic pathway. The extract potential against Staphylococcus aureus, Salmonella paratyphi A, triggered cell death with increased phosphatidyl serine Klebsiella pneumonia, Pseudomonas aeruginosa, Shigella sonnei, externalization, DNA breaks and significant morphological Escherichia coli and Salmonella typhimurium and showed very apoptotic characteristics in the MCF cells (Ho et al., 2011), while good antibacterial activity, but the methanolic extract was the aqueous extract of leaves of E. scaber has been subjected to found to be the most effective against the tested organisms in vivo study as described in the later section. (Jenny et al., 2012). The methanol and aqueous extract of E. scaber leaf was tested on selected bacterial pathogens such as In vivo antitumor activity E. coli, S. aureus, Streptococcus pyogenes, P. aeruginosa, Leuconostoc From the in vitro antitumor studies, it has been observed that lactis, Bacillus subtilis, Proteus vulgaris and Salmonella typhi. The deoxyelephantopin is the major sesquiterpenoids isolated antibacterial activity of methanolic extract of E. scaber journal of applied biomedicine 12 (2014) 49–61 55

Table 2 – Sesquiterpene lactones and extract producing cytotoxicity against various cell lines. Extract/sesquiterpene lactones Cell lines References

Aqueous extract Dalton's ascitic lymphoma (DAL) Rajkapoor et al. (2002) Ethanolic extract Breast cancer cell line (MCF-7) Ho et al. (2011)

Deoxyelephantopin In vitro study: human hepatocarcinoma cell line (SMMC-7721), human Xu et al. (2006), cervical carcinoma (HeLa), human colon carcinoma (Caco-2), melanoma Geetha et al. (2012), derived cell line (MEXF 394NL), mammary cancer cell line (MAXF Than et al. (2005), 401NL), human prostate carcinoma cell (PC-3), human nasopharyngeal Su et al. (2009, 2011) carcinoma epithelial cell (CNE), human acute promyelocytic leukemia and Huang et al. (2010) cell (HL-60) In vivo study: Dalton's ascitic lymphoma (DAL), human cervical cancer xenograft model, murine mammary adenocarcinoma cell line (TS/A), human breast adenocarcinoma cell line (MCF-7), human breast skin fibroblast cell line (CCD966SK), metastatic human breast cancer cell line (MDA-MB-231)

Isodeoxyelephantopin Human hepatocarcinoma cell line (SMMC-7721), human cervical Xu et al. (2006), carcinoma (HeLa), human colon carcinoma (Caco-2), Dalton's ascitic Geetha et al. (2012), lymphoma (DAL), human chronic myeloid leukemia (KBM-5), lung and Ichikawa et al. (2006) adenocarcinoma (H1299), human promyelocytic leukemia (HL60), human embryonic kidney carcinoma (A293), human breast adenocarcinoma (MCF-7), human multiple myeloma (MM.1S), and human multiple myeloma cell lines (U266) Scabertopin Human hepatocarcinoma cell line (SMMC-7721), human cervical Xu et al. (2006) carcinoma (HeLa) and human colon carcinoma (Caco-2) Isoscabertopin Human hepatocarcinoma cell line (SMMC-7721), human cervical Xu et al. (2006) carcinoma (HeLa), and human colon carcinoma (Caco-2) Elescaberin Human hepatocarcinoma cell line (SMMC-7721) Liang et al. (2008) 17,19-Dihydro-deoxyelephantopin Melanoma derived cell line (MEXF 394NL) and renal cancer cell line (RXF Than et al. (2005) 944L) Iso-17,19-dihydrodeoxyelephantopin Melanoma derived cell line (MEXF 394NL), lung cancer (LXFL 529L) Than et al. (2005)

indicated that the crude solvent extracts possess prominent against eleven ATCC (American Type Culture Collection) antibacterial activity toward the gram positive bacterium bacterial isolates. Concentration of 1, 2 and 4 mg/ml of ethyl S. pyogenes than gram negative bacteria. There was no marked acetate and petroleum ether extract was used. Ethyl acetate activity against gram positive and gram negative bacteria extract of the plant showed growth inhibitory effect at when compared to both solvent extracts except methanol 4 mg/ml concentration in all the bacterial isolates tested extract against S. pyogenes (Sureshkumar et al., 2004; Kama- except K. pneumonia where it showed 75% inhibition. Lower lakannan et al., 2012). In addition leaf ethanolic extracts of concentration of the extract showed concentration-depen- E. scaber demonstrated the highest zone of inhibition against dent inhibitory effect. At 2 mg/ml 50% inhibition took place, pathogens viz., Enterococcus faecalis, Proteus mirabilis, S. typhi whereas at 1 mg/ml it was completely ineffective. Inhibitory and Enterobacter spp. In case of root ethanolic extracts effect of petroleum ether extract at all the three concentra- E. scaber illustrated the highest zone of inhibition against tions was not found on any of the cultures except Micrococcus three pathogens, viz., S. aureus, E. coli and P. aeruginosa. luteus where it showed 50% inhibition at 2 mg/ml and The chlorofrom extracts of E. scaber root showed the complete inhibition at 4 mg/ml. Hence the study confirmed highest zone of inhibition against Bacillus cereus (Anitha that the ethyl acetate extract of E. scaber has antimicrobial et al., 2012). potential (Avani and Neeta, 2005), whereas the hydro- E. scaber whole plant extracts were screened against alcoholic, hexane, ethyl acetate and methanol extracts of extended spectrum b lactamase (ESBL) producing methicillin whole plant of E. scaber were tested for its antibacterial resistant S. aureus (MRSA) bacterial strain. Fractionation of potential against S. aureus, E. coli, K. pneumonia, P. aeruginosa plant extracts revealed that the acetone fraction showed good and S. typhimurium. The study observed that the highly activity, while less activity was found in the methanol and significant zone of inhibition was exhibited by the ethyl hexane fractions (Jasmine et al., 2007a). Though the acetone acetate and hexane fractions of E. scaber against all tested extract exhibited higher inhibitory activity, yet no inhibitory organisms (Gangarao et al., 2012). The aqueous extract of zones were observed against Pseudomonas spp., while the E. scaber has also been reported to have considerable methanol and hexane extracts of E. scaber were effective antibacterial activity against the cariogenic bacterium, against Pseudomonas spp. The plant showed similar activity Streptococcus mutans (Chen et al., 1989). against gram-positive and gram-negative bacteria, which The novel terpenoid isolated from the acetone extract of maybeindicativeofthepresenceofbroadspectrumantibiotic whole plant of E. scaber has shown significant antibacterial compounds in E. scaber (Jasmine et al., 2007b). The petroleum activity against S. aureus by inhibiting autolysin (Daisy et al., ether and ethyl acetate extracts of whole plant were tested 2008). 56 journal of applied biomedicine 12 (2014) 49–61

Antifungal activity Battu et al. (2012) evaluated the hexane, ethyl acetate and ethanol fraction of whole plant of E. scaber against carbon Many researchers have reported the antifungal activity of tetrachloride-induced hepatic damage in rats and showed various extracts of E. scaber. It is evident that the antibacterial significant hepatoprotection by ethanol fraction compared to and antifungal activity study of E. scaber has been mostly other fraction. In addition, the ethanolic leaf extract of E. scaber performed on total extract and not on the sesquiterpene against alcohol induced liver damage in mice showed lactone compound. Hence there is little scope to derive a promising hepatoprotection activity. The ability of E. scaber conclusion about the efficacy of sesquiterpene lactone of treated mice to cope with the oxidative stress induced by E. scaber in this context. Other constituents of this plant may alcohol could be accountable to the antioxidant capacity of the also be responsible for the activity. herb and it most effectively restored the liver damage to near Duraipandiyan and Ignacimuthu (2011) used hexane, ethyl normal (Ho et al., 2012). acetate and methanol extract of root of E. scaber for its A sesquiterpene lactone, deoxyelephantopin isolated from antifungal activity. The fungal strain used were Trichophyton E. scaber plant also demonstrated the potential hepatoprotec- rubrum MTCC 296, T. rubrum 57/01, T. mentagrophytes 66/01, T. tive effect against lipopolysaccharide/D-galactosamine (LPS/D- simii 110/02, Epidermophyton floccosum 73/01, Scopulariopsis sp. GalN)-induced fulminant hepatitis. Deoxyelephantopin acts 101/01, Aspergillus niger MTCC 1344, Botrytis cinerea, Curvularia by modulating multiple molecular targets or signaling path- lunata 46/01, Magnaporthe grisea and Candida albicans MTCC 227. ways that counteract inflammation during the progression of Hexane extract did not show antifungal properties against fulminant hepatitis and may serve as a novel lead compound tested fungi while ethyl acetate and methanol extract for future development of anti-inflammatory or hepatopro- inhibited only few tested fungi such as T. mentagrophytes, tective agents (Huang et al., 2013). E. floccosum and T. simii. The methanol and aqueous extracts of E. scaber leaf were Antidiabetic activity tested on selected the four fungal strains A. niger, Aspergillus flavus, Rhizopus indicus and Mucor indicus. The antifungal Although there has not been any strong ethnomedical claim activities of both the leaf extracts of E. scaber were determined for the use of E. scaber in treating diabetes, researchers have against four fungal strains. The antifungal activity was explored the potential of E. scaber as an antidiabetic agent. observed in a dose-dependent manner, and highest activity In streptozotocin-induced diabetic rats, methanol, hexane was observed with methanolic extract against M. indicus and ethyl acetate extracts of E. scaber leaves were tested (32 mm) and minimum activity was recorded against R. indicus and proved to have significant hypoglycemic properties. (14 mm). There was no activity observed in aqueous extract The effective dosage of various extracts was fixed to be against the tested fungus (Kamalakannan et al., 2012). While 250 mg/kg b.w./day. These extracts improved the biochemical against Candida bombii, C. tropicalis and C. utilis the hydroalco- parameter assessed and also brought about regeneration of b- holic, hexane, ethyl acetate and methanol extracts of whole cells of pancreas with increasing insulin levels (Daisy et al., plant of E. scaber were tested for its antifungal potential and it 2009b). Whereas in the same experimental model, hexane was observed that the highly significant zone of inhibition was extract of E. scaber root brought about a better hypolipidemic exhibited by the ethyl acetate and hexane fractions of E. scaber potential and a re-establishment of renal functions. The (Gangarao et al., 2012). extract produced a significant dose-dependent decrease in the levels of total cholesterol, triacylglycerol, and low-density Hepatoprotective activity lipoprotein-cholesterol, with a significant increase in the level of high-density lipoprotein-cholesterol, and reported the There have been ethnomedical references for the use of restoration of renal functions back to near normal (Daisy E. scaber in certain liver ailments and the study of hepatopro- and Priya, 2010). While the acetone extract of E. scaber plant tective activity also proves the claims. reduced the blood glucose levels in streptozotocin-induced The aqueous extract of E. scaber has been treated against diabetic rats significantly by potentiating the insulin effect of three experimental models such as lipopolysaccharide, plasma by increasing either the pancreatic secretion of insulin D-galactosamine and acetaminophen (APAP) induced hepatic from the b cells of islets of Langerhans or its release from damage in rats. The serum glutamate-oxalate-transaminase bound insulin. Further fractionation of the acetone extract (SGOT) and the serum glutamate-pyruvate-transaminase yielded a new steroid, 28Nor-22(R) witha 2,6,23-trienolide, (SGPT) level have been decreased so that the hepatic lesions which demonstrated a significant antidiabetic activity by and leukocyte infiltration were prominently reduced by reducing the elevated blood glucose levels and restoring the E. scaber treatment. The mechanism of the hepatoprotective insulin levels in the same experimental model (Daisy et al., effect by E. scaber was mainly due to the suppression of p38 2009a; Jasmine and Daisy, 2007). However the methanol MAPK and to a lesser degree of COX-2 pathway (Lin et al., 1995; extract of E. scaber root is more effective than that of E. scaber Hung et al., 2011). The methanol extract of E. scaber root leaf in correcting the metabolic disorders. The insulin fi fi against CCl4-induced hepatic necrosis showed signi cant de ciency has adverse effect on glucose oxidation in liver hepatoprotective activity. CCl4 causes decrease in the level of and skeleton muscles of diabetic rats and this metabolic antioxidant enzyme like superoxide dismutase (SOD) and disorder can be corrected by E. scaber (Daisy and Jasmine, 2008). catalase. It has been prevented and thus hepatic injury is Daisy et al. (2007) reported a comparative study between repaired by the administration of methanolic extract of aqueous extract of E. scaber root and leaf against alloxan- E. scaber root. induced hyperglycemic rats and observed that aqueous root journal of applied biomedicine 12 (2014) 49–61 57

extract of E. scaber shows better hypoglycemic action by pathway may contribute to antiplatelet activity of lupeol, a reducing the blood glucose level when compared with leaf terpenoid compound. Hence the isolated triterpenoid com- extract. pound has higher antiplatelet activity; therefore, the con- sumption of E. scaber products may help to prevent or treat Antioxidant activity cardiovascular disorders such as thrombosis (Sankaranaraya- nan et al., 2010). The methanolic extract of E. scaber root has been proven to be an efficient antioxidant in the in vitro model. The superoxide Other activities generation by the reaction of photo-reduced riboflavin and oxygen is inhibited by the methanolic extract of E. scaber root. Ethanolic extract of E. scaber leaves has shown significant The generation of malondialdehyde and related substances antiasthmatic activity; wound healing and nephroprotective from lipid extract react with thiobarbituric acid was found to activities along with its prominent antiplatelet activity. be inhibited by the methanolic extract of E. scaber root. The Deoxyelephantopin isolated from the ethanolic extract of E. degradation of deoxyribose to TBARS by the hydroxyl radicals scaber leaves promotes significant wound healing activity by 3+– – – generated from Fe ascorbate EDTA H2O2 system was increasing cellular proliferation, formation of granulation markedly decreased by the methanolic extract of E. scaber tissue, and synthesis of collagen and by increasing in the rate root (Sheeba et al., 2012). However the hydroalcoholic, hexane, of wound contraction (Singh et al., 2005). ethyl acetate and methanol extracts of whole plant of E. scaber In spite of this, the ethanol extract of E. scaber leaves were tested for its antioxidant potential and were found to (250 mg/kg and 500 mg/kg) also significantly decreased the possess concentration-dependent inhibition using DPPH, bronchospasm induced by histamine and acetylcholine and superoxide and hydroxyl radicals scavenging activity (Gang- protected mast cell degranulation compared to that in control arao et al., 2012). groups. It also decreased the histamine-induced constriction on isolated guinea pig trachea in a dose-dependent manner. Anti-inflammatory and analgesic activities Antiasthmatic action of the E. scaber could be due to its antihistaminic, anticholinergic and mast-cell-stabilizing prop- The aqueous extract of E. scaber leaves has good analgesic erty (Sagar and Sahoo, 2012). It also restored the elevated activity and weaker anti-inflammatory activity (Ruppelt et al., serum urea and creatinine level, indicating its significant 1991). In another study Poli et al. (1992) reported that the nephroprotective effect (Bhusan et al., 2012). aqueous and hydroalcoholic extracts of whole plant did not These studies relate the proof of ethnomedical claims of E. possess analgesic, diuretic, antipyretic or anti-inflammatory scaber toward the use in asthma and urinary problems. activities. However these extracts when administered intra- venously reduced blood pressure and heart rate in rats. The Toxicological studies aqueous extract decreased the intestinal transit time in mice, while the hydro-alcoholic extract increased it. Later in Oral administration of either aqueous or hydroalcoholic contradiction to the report of Poli et al. (1992) and Tsai and extract of whole plant of E. scaber up to 6 g/kg, p.o. produced Lin (1999) reported that the aqueous extracts of E. scaber whole neither any abnormal effect nor any mortality (Poli et al., 1992; plant exhibited significant anti-inflammatory effects by Sankar et al., 2001). However intraperitoneal injections of inhibiting the development of chronic joint swelling induced aqueous (0.03–3 g/kg) or hydro-alcoholics (0.1–3 g/kg) induced by CFA (complete Freund's adjuvant) and also significantly writhing, loss of muscle tone, ataxia, prostration and death. inhibited the carrageenan-induced acute arthritis. The hydro- Hence the acute toxicity tests indicated that the LD50 values for alcoholic extract of aerial part of E. scaber showed significant the extracts were higher than 2 g/kg and 6 g/kg when given i.p. anti-inflammatory activity by reducing carrageenan-induced and p.o., respectively, thus revealing a low acute toxicity (Poli pedal edema (57%) and formalin induced pedal edema in rats et al., 1992). (58%) which is comparable to the activity of diclofenac (Sankar Singh et al. (2005) reported that the maximum tolerated et al., 2001). dose for the aqueous and ethanol extracts of E. scaber was 3 g/ kg b.w. and for the isolated compound deoxyelephantopin, it Antiplatelet activity was 40 mg/kg b.w. Hence, 1/10 of these doses, i.e., 300 mg/kg b. w. of aqueous or ethanol extract and 4 mg/kg b.w. of the Ethanolic extract of E. scaber leaves possesses significant compound, was selected for the topical evaluation of wound antiplatelet activity. Triterpenoid compound has been isolated healing efficacy. Whereas the acute toxicity studies revealed from the E. scaber leaves and the different concentrations of that the ethanol extracts as well as acetone extract of whole triterpenoid compound from this plant investigated for the plant of E. scaber did not show mortality and any sign of inhibitory effect on platelet aggregation in vitro. Triterpenoid toxicity at higher dose (2000 mg/kg and 6000 mg/kg). The result compound significantly inhibited thrombin-induced platelet clearly indicated the non-toxicity of plant extract (Daisy et al., aggregation. The lower concentration (25 mg/ml) of triterpe- 2009a; Battu et al., 2012; Sagar and Sahoo, 2012). Ho et al. (2012) noid compound was found to be a weak inhibitor and higher observed no mortality after 14 days of treatment with a limited concentration (100 mg/ml) was found to be a strong inhibitor of dose of 5000 mg/kg b. w. of ethanolic extract of leaves of thrombin-induced platelet aggregation. The inhibitory mech- E. scaber. Oral administration of the ethanolic extract produces anism of different concentrations on analysis showed that the no signs of abnormalities or gross lesions in necropsy findings; inhibition of extracellular signal-regulated kinase (ERK 1/2) no statistically significant differences in body weight and 58 journal of applied biomedicine 12 (2014) 49–61

weight gain were noted between the treated group and the They claimed a topical solution for the treatment of acne untreated control group. Thus, LD50 of E. scaber could not be lesion. The formulation is applied using a cotton swab to the determined and the extract could be regarded as nontoxic for acne area and creates a vapour flux penetration of the herbal oral consumption up to a concentration of 5000 mg/kg b.w. in extracts, which loosens black heads of acne and treats the acne mice. by killing the bacteria and removing the inflammatory During the literature survey no reports were found on the elements in the pilosebaceous unit within 3–5 days. chronic toxicity studies, clinical studies and reproductive toxic Daisy (2007) has filed patent for a novel steroid from the effects of E. scaber. Further studies of the extract and the active acetone extract of E. scaber possessing antidiabetic activity in constituents of E. scaber need to be carried out for its evaluation streptozocin-induced diabetic rat model. The compound was as a potential therapeutic agent. identified as withanolide and characterized as 28Nor-22(R) witha 2,6,23-trienolide. Shyur (2012) has patented the isolated constituent, deox- Patentability potential of E. scaber yelephantopin and other sesquiterpene lactones (isodeoxye- lephantopin, scabertopin and isoscabertopin) from the E. Literature survey of E. scaber reveals many significant activi- scaber plant for the treatment of melanoma. They claimed that ties. It shows significant pharmacological activities, especially deoxyelephantopin and their analogs act by inhibiting in cases of anticancer, hepatoprotective, antidiabetic, antimi- proliferation, migration and/or metastasis of melanoma cell crobial, antioxidant, antipyretic, anti-inflammatory and anti- by comparing the data with that of cisplatin. Deoxyelephan- asthmatic activities. Deoxyelephantopin has been found to be topin and cisplatin exhibited dose-dependent inhibition of B16 a very promising compound for the treatment of cancer. cell proliferation and showed little or no toxicity on normal Huang et al. (2010) reported that deoxyelephantopin was human melanocytes. They also claimed for the synergistic effective and superior to the breast cancer drug paclitaxel effect of deoxyelephantopin with cisplatin and observed against TS/A mammary tumor growth and lung metastasis, for variable degrees of synergistic cytotoxicity in B16 melanoma increased overall survival of mice with mammary tumors. cell. Geetha et al. (2012) revealed that deoxyelephantopin and isodeoxyelephantopin are not cytotoxic to normal human Commercialization potential of E. scaber lymphocytes and only the proliferating cells of DLA tumor cells were affected. Hence the compound could be used in regimens for treating tumors with extensive proliferative potencies. Till date, at least six patents of herbal formulations containing Many herbal formulations with the presence of E. scaber as E. scaber as one of the important ingredients have been an important active ingredient have been patented for reported. The active constituents such as deoxyelephantopin, different therapeutic purposes. The use of deoxyelephantopin isodeoxyelephantopin, scabertopin and isoscabertopin isolat- and its analogues has also been patented for the treatment of ed from E. scaber have shown very significant anticancer melanoma. Although there are a number of publications and activity. Surprisingly there have not been any reports of the patents, yet the potential of the plant E. scaber, their extract clinical studies in these regards. Scientific community is trying and isolated sesquiterpene lactones has not been put to proper to optimize the formulation containing E. scaber to exploit the use as a drug candidate. therapeutic potential of this plant in the international market Hozumi et al. (1995) have patented antiviral property of a (Ho et al., 2009). crude drug. A number of crude drugs have been selected for their antiviral activity and the aqueous extract of leaves of Conclusion E. scaber has been reported to be effective against Polio and Measles virus at the concentration range of 100–500 mg/ml. Solanki (2003) has drugs containing formulation with 5% of E. scaber Linn. family Asteraceae is a small herb spread all over root and stem of E. scaber for the treatment of cancer, the world. It has been used as a medicine since a long period of particularly myelomas. The formulation comprising of other time in almost all countries where it grows, and many herbal drugs along with E. scaber was claimed to be beneficial to ethnomedical claims have been scientifically proven by patients with myeloma including both solitary and multiple conducting extensive research on this plant. About a dozen myelomas through preventing the development of drug of multifarious activities ranging from anticancer, antibacte- resistance to cancer, promoting patient's health and reducing rial, antifungal, hepatoprotective, antidiabetic, antioxidant, side effect after chemotherapy and radiotherapy. In another anti-inflammatory, analgesic, antiplatelet, antiasthamatic patent, Solanki (2004) used E. scaber along with other ten herbs and nephroprotective to that of wound healing have been for treatment of cancer, particularly for squamous cell reported in the literature. carcinomas, tumors and other metastatic state including lung E. scaber has been reported to contain novel sesquiterpene cancer. The preparation is preferably formulated for adminis- lactones in the specific extracts such as chloroform, acetone, tration to patients as a liquid or syrup but could also be methanol, ethanol and aqueous extracts. The major sesqui- administered as a tablet or capsule, and the dose selected for terpenoids that contribute to the above biological activities therapy is 450 mg three times per day. have been identified as deoxyelephatopin, isodeoxyelephan- Lee (2005) has patented a formulation comprising of topin, scabertopin, isoscabertopin and few others. However, E. scaber (0.1–5%) along with other six herbal extracts for the the plant contains other constituent such as triterpenoids, viz. treatment of acne (comedones and pimple) and cystic acne. lupeol, betulinic acid, ursolic acid, and epifridelanol. Steroidal journal of applied biomedicine 12 (2014) 49–61 59

constituents may also have their role in certain specific Challenge and Scope Natural Products in Medicinal – pharmacological activities. Chemistry. 313 334. Chen, C.P., Lin, C.C., Namba, T., 1989. Screening of Taiwanese E. scaber and its phytoconstituents, especially sesquiter- crude drugs for antibacterial activity against Streptococcus pene lactones, have been explored to prove many of the mutans. J. Ethnopharmacol. 27, 285–295. ethnomedical claims as evident from the results of various Chuakul, W., Soonthornchareonnon, N., Sappakun, S., 2006. pharmacological studies. However, the data of clinical studies Medicinal used in Kungkrabaen royal development on the utility of E. scaber and its extracts as herbal medicine or study center, Chanthaburi province. Thai J. Phytopharm. 13 its compounds as drugs for the treatment of various diseases (1), 27–42. have not been available. The efforts in this direction may Daisy, P., Rayan, N.A., Rajathi, D., 2007. Hypoglycemic and other related effects of Elephantopus scaber extracts on alloxan further explore the possibility of E. scaber and its phytocon- induced diabetic rats. J. Biol. Sci. 7 (2), 433–437. stituents as a potential drug. Daisy, P., 2007. A novel steroid from Elephantopus scaber L. an ethnomedicinal plant with antidiabetic activity. Indian Patent application 809/CHE/2007. Conflict of interest Daisy, P., Mathew, S., Suveena, S., Rayan, N.A., 2008. A novel terpenoid from Elephantopus scaber – antibacterial activity on Staphylococcus aureus We declare that we have no conflict of interest. : a substantiate computational approach. Int. J. Biomed. Sci. 4 (3), 196–203. Daisy, P., Jasmine, R., 2008. Role of Elephantopus scaber on the glucose oxidation in liver and skeletal muscles of strptozotocin induced diabetic adult male rats. Res. J. Med. Acknowledgements Plant 2 (1), 22–27. Daisy, P., Jasmine, R., Ignacimuthu, S., Murugan, E., 2009a. A The authors acknowledge with thanks the financial support as novel steroid from Elephantopus scaber L. an ethnomedicinal plant with antidiabetic activity. Phytomedicine 16, 252–257. JRF from the H'ble Vice Chancellor, Guru Ghasidas Vishwavi- Daisy, P., Vargese, L., Priya, C.E., 2009b. Comparative studies on dyalaya, Bilaspur and technical support from the Head of the different leaf extracts of Elephantopus scaber. on STZ- School of Pharmaceutical Sciences, Bilaspur, for the providing induced diabetic rats. Eur. J. Sci. Res. 32 (4), 304–313. of laboratory and library facilities. Daisy, P., Priya, C.E., 2010. Hypolipidemic and renal functionality potentials of the hexane extract fractions of Elephantopus scaber Linn. Int. J. Biomed. Sci. 6 (3), 241–245. references Desilva, L.B.D., Herath, W.H.M.W., Jennings, R.C., Mahendran, M., Wannigama, G.E., 1982. A new sesquiterpene lactone from Elephantopus scaber. Phytochemistry 21, 1173–1175. Duraipandiyan, V., Ignacimuthu, S., 2011. 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