<?xml version="1.0" encoding="UTF-8"?><!DOCTYPE article PUBLIC "-//NLM//DTD JATS (Z39.96) Journal Archiving and Interchange DTD v1.1d1 20130915//EN" "JATS-archivearticle1.dtd">
<article xmlns:xlink="http://www.w3.org/1999/xlink" article-type="review-article" dtd-version="1.1d1">
  <front>
    <journal-meta>
      <journal-title-group>
        <journal-title>Biomedical Research and Therapy</journal-title>
      </journal-title-group>
      <issn pub-type="epub" publication-format="electronic">2198-4093</issn>
      <publisher>
        <publisher-name>BioMedPress</publisher-name>
      </publisher>
    </journal-meta>
    <article-meta>
      <article-id pub-id-type="doi">10.7603/s40730-014-0018-1</article-id>
      <article-categories>
        <subj-group subj-group-type="display-channel">
          <subject>Review</subject>
        </subj-group>
        <subj-group subj-group-type="heading">
          <subject>Biomedical Research and Therapy</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Lawsonia inermis (L.): A perspective on anticancer potential of Mehndi/Henna</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <name>
            <surname>Kumar Singh</surname>
            <given-names>Dhananjay</given-names>
          </name>
          <xref ref-type="aff" rid="aff1"/>
        </contrib>
        <contrib contrib-type="author" corresp="yes">
          <name>
            <surname>Luqman</surname>
            <given-names>Suaib</given-names>
          </name>
          <xref ref-type="aff" rid="aff1"/>
          <xref ref-type="aff" rid="aff2"/>
          <xref ref-type="corresp" rid="cor1">*</xref>
        </contrib>
        <aff id="aff1">
          <institution>Molecular Bioprospection Department</institution>
        </aff>
        <aff id="aff2">
          <institution>Academy of Scientific and Innovative Research (AcSIR), CSIR-Central Institute of Medicinal and</institution>
        </aff>
      </contrib-group>
      <author-notes>
        <corresp id="cor1"><label>*</label>For correspondence: <email>s.luqman@cimap.res.in</email></corresp>
        <fn fn-type="con" id="equal-contrib">
          <label>*</label>
          <p>These authors contributed equally to this work</p>
        </fn>
      </author-notes>
      <pub-date date-type="pub" publication-format="electronic">
        <day>07</day>
        <month>09</month>
        <year>2014</year>
      </pub-date>
      <volume>1</volume>
      <issue>4</issue>
      <fpage>112</fpage>
      <lpage>120</lpage>
      <history>
        <date date-type="received">
          <day>22</day>
          <month>08</month>
          <year>2014</year>
        </date>
        <date date-type="accepted">
          <day>29</day>
          <month>08</month>
          <year>2014</year>
        </date>
      </history>
      <permissions>
        <copyright-statement>Copyright: &#169; The Author(s) 2014</copyright-statement>
        <copyright-year>2014</copyright-year>
        <license license-type="open-access" xlink:href="http://creativecommons.org/licenses/CC-BY/4.0">
          <license-p>This article is distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0) which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.</license-p>
        </license>
      </permissions>
      <abstract>
        <p>Incidence of cancer is growing swiftly worldwide and sparse supply of anticancer drugs; unaffordable cost and its lethal effect have shown the way to adopt complementary and alternative medicine for the treatment and/or prevention of cancer. The isolation of anti-cancer alkaloids vinblastine, vincristine and podophyllotoxins during 1950s prompts research on anticancer agents from plant origins. Lawsonia inermis (L.) popularly known as Mehndi or Henna, is a cosmetically renowned plant of the oriental region possesses diverse pharmacological activity including anti-carcinogenic, antimicrobial, anti-inflammatory, analgesic, antipyretic, hepatoprotective, anti-tuberculostatic. In search of new anticancer drugs from natural sources many researchers have reported anticancer and chemopreventive properties of Henna extracts/compounds in their pre-clinical studies. Lawsone, one of the major constituent of henna, is used as a starting material in the synthesis of a variety of clinically valuable anticancer drugs such as atovaquone, lapachol and dichloroallyl lawsone. This plant contain other chemicals such as isoplumbagin, apigenin, apigenin glycosides, luteolin, luteolin-7 glucosides, p-coumarin and lupeol among which many are reported for their cytotoxicity and chemopreventive activity against different type of cancer cell. Here in this review, we are reporting a palingenesis of information regarding anticancer potential of Mehndi/Henna. We have included maximum available information from its in vitro and in vivo studies by referring different websites, text-books, notes, and articles, abstract, summary and consulting worldwide accepted scientific databases. The present review recapitulates some important findings on the anticancer potential of Mehndi/Henna and to a great extent more work has to be undertaken to explore its novel target(s). Future investigation on novel molecules from Mehndi/Henna may offer great hope for discovering new cancer chemotherapeutic and/or chemopreventive agents from this miraculous plant.</p>
      </abstract>
      <kwd-group>
        <kwd>Anticancer</kwd>
        <kwd>chemoprevention</kwd>
        <kwd>Henna</kwd>
        <kwd>Lawsone</kwd>
        <kwd>Lawsonia inermis</kwd>
        <kwd>phytochemistry</kwd>
      </kwd-group>
    </article-meta>
  </front>
  <body>
    <sec id="s1">
      <title>Introduction</title>
      <p>The prevalence of cancer is speedily growing worldwide and rank second after cardiovascular diseases targeting both developed and developing countries. Limited supply of anticancer drugs, unaffordable cost of treatments, and lethal adverse effect of several available drugs have shown the way to adopt complementary and alternative medicine for the treatment and/or prevention of cancer <xref ref-type="bibr" rid="ref16">Cragg et al., 1997</xref><xref ref-type="bibr" rid="ref35">McClellan et al., 2011</xref>. Almost twenty five percent of the modern medicine used today originates from plants and the examples include taxol from Taxus baccata (Yew), vincristine and vinblastine from Catharanthus roseus (Sadabahar), podophyllotoxin from Podophyllum peltatum (Mayapple), aspirin from Sahennax species (Willow bark), digitalis fromDigitalis purpurea (Foxglove), pilocarpine from Pilocarpus jaborandi (Jaborandi or Indian hemp). Since the dawn of civilization, plants are essential element of human society and used extensively in folk medicine for the treatment of innumerous ailments. Since then several species of plants have become a part of various indigenous system of treatment such as Ayurveda, Unani, Siddha and Homeopathy collectively known as AYUSH. Plants, rich in secondary metabolites and essential oils have been studied during the last few decades for potential source of drug. Today, it is ballparked that a propos of 70-95 % people dwelling in developing nation relies on traditional medicines for their primary health care <xref ref-type="bibr" rid="ref18">Dahanukar et al., 2000</xref>. Drugs from plant origin posturing to become source for medicine have led to an unexpected augmentation in the number of herbal industries <xref ref-type="bibr" rid="ref32">Kirtikar and Basu, 2005</xref>. The isolation of anti-cancer compounds such as vinblastine, vincristine from Catharanthus roseus and podophyllotoxins fromPodophyllum peltatum in 1950s promoted the researchers to explore anticancer agents from plant sources <xref ref-type="bibr" rid="ref11">Cassady and Douros, 1980</xref><xref ref-type="bibr" rid="ref15">Cragg and Newman, 2005</xref><xref ref-type="bibr" rid="ref46">Shoeb,2005</xref>. Out of the available anticancer drugs in the market, two-third is either of natural origin or simple modification of the natural product <xref ref-type="bibr" rid="ref16">Cragg et al., 1997</xref>.</p>
      <p>Lawsonia inermis L. (Lythraceae), a monotypic genus, popularly known as &#8216;Mehndi&#8217; or&#8216;Henna&#8217; is renowned as a cosmetic as well as medicinal agent in the Oriental parts of the world since time immemorial. The plant extracts and purified constituent of henna in folklore accounts for a variety of activities including antibacterial <xref ref-type="bibr" rid="ref34">Malekzadeh, 1968</xref>, antifungal <xref ref-type="bibr" rid="ref50">Tripathi et al., 1978</xref>, antioxidant and immunomodulatory (Hsouna et al., 2010)<xref ref-type="bibr" rid="ref37">Mikhaeil et al., 2004</xref>, hepatoprotective <xref ref-type="bibr" rid="ref5">Anand et al., 1992</xref>, analgesic, anti-inflammatory and antipyretic <xref ref-type="bibr" rid="ref3">Ali et al., 1995</xref>, and cytotoxic <xref ref-type="bibr" rid="ref4">Ali and Grever, 1998</xref>. The bactericidal and fungicidal action of this plant has been attributed through its tanning effect <xref ref-type="bibr" rid="ref51">Wessjohann et al., 2003</xref> and it has been confirmed that henna is neither an allergen nor a carcinogen <xref ref-type="bibr" rid="ref38">Nayak et al., 2007</xref>. The key coloring agent present in henna leaves is a red-orange pigment lawsone (2- hydroxy-1, 4-naphthoquinone) <xref ref-type="bibr" rid="ref2">Al-Tufail et al., 1999</xref><xref ref-type="bibr" rid="ref33">Lekouch et al., 2001</xref>, which makes this plant useful for dying of hair, as well as to color palms, fingers, fingernails and soles <xref ref-type="bibr" rid="ref10">Cartwright, 2006</xref><xref ref-type="bibr" rid="ref26">Hanna et al., 1998</xref>. Lawsone is also a suitable reagent for the detection of latent fingermarks on paper, as contact evidence in criminology <xref ref-type="bibr" rid="ref31">Khan and S., 2010</xref>. Lawsone (2-hydroxy-1, 4-naphthoquinone) is a starting material in the synthesis of many clinically useful anticancer compounds such as atovaquone, lapachol and dichloroallyl lawsone <xref ref-type="bibr" rid="ref42">Pradhan et al., 2012</xref>.</p>
      <p>In Ayurveda and Unani medicine, Henna has been considered as a source of non-toxic therapeutic agent for blood tonic, cancer, infectious disease, inflammation, tuberculosis, tumors and wounds when; given as single preparation of henna decoction or extract or as blended with other molecules. Translation of Henna compounds and its derivatives to modern drug discovery strategy results to potential new molecule for specific therapeutic agents. The description of lawsone derivatives in our review offers agreeable substantiation for the usefulness of some of these molecules against certain type cancers. It is worthy to notice that lawsone itself has significant antioxidant and anti-inflammatory activity that could be major characteristic of numerous anticancer phytochemicals.</p>
      <p>Although Mehndi/Henna extracts and constituents are reported for its pharmacological properties but little attention has been paid to explore its anticancer potential. Therefore, in this review we prepared a palingenesis of information regarding anticancer reports on mehndi/henna by providing maximum available information from its In vitro and in vivo studies.</p>
    </sec>
    <sec id="s2">
      <title>Information retrieval</title>
      <p>Imperative information for the compilation of review was acquired from published literature in form of abstracts, articles, books, notes, peer reviewed papers, summary, texts etc. by using key words &#8216;Lawsonia inermis&#8217;, &#8216;Mehndi and/or &#8216;Henna as anticancer agent&#8217;, &#8216;anticancer activity of mehndi/henna&#8217;, &#8216;cytotoxicity of mehndi/henna&#8217;, &#8216;Extracts/ compounds in Mehndi/henna as anticancer agent&#8217; &#8216;Anticancer/cytotoxicity activities of mehndi/henna extract and essential oil&#8217;, &#8216;Mehndi/henna and cancer cell lines&#8217;, &#8216;Mehndi/henna and cancer/tumor&#8217;, &#8216;chemopreventive properties of mehndi/henna&#8217;. Also a comprehensive bibliographic search on Mehndi/henna was carried out during March 2013-March 2014 exploring the worldwide accepted scientific databases of NISCAIR, SCIELO, PUBMED, SCOPUS, INFLIBNET, Sci-Finder, Science Direct and Google Scholar. Compilation of the information retrieved was done arbitrarily for the preparation of palingenesis of the review under the appropriate headings.</p>
    </sec>
    <sec id="s3">
      <title>Phytochemistry</title>
      <p>Noticed by researchers, Mehndi/Henna got its popularity due to presence of a unique chemical named lawsone. Other group of molecules reported from this plant include quinones, phenylpropanoids, flavonoids, terpenoids, phenolics, fatty acids, carbohydrates, proteins, tannins, alkaloids, xanthones, coumarin, glucosides, naphthoquinone, saponins, triterpenoids, sterols and dioxin derivatives. Some potent bioactive like isoplumpagin (a naphthaquinone from bark), lupeol, 30-norlupan-3-ol-20-one, betuhennan, betuhennanic acid and n-tridecanoate (bark), phenolic glycosides, lawsoniaside, &#946; -sitosterol and stigmasterol (leaves) have been reported from Mehndi/Henna plant <xref ref-type="bibr" rid="ref8">Bhardwaj et al., 1980</xref><xref ref-type="bibr" rid="ref9">Bhardwaj et al., 1978</xref><xref ref-type="bibr" rid="ref13">Chakrabortty et al.,1980</xref><xref ref-type="bibr" rid="ref22">Gupta et al., 1992</xref><xref ref-type="bibr" rid="ref24">Gupta et al., 1993</xref><xref ref-type="bibr" rid="ref49">Takeda and Fatope, 1988</xref>, 24-beta ethyl cholest-4-en-3-beta-ol have also been reported from the roots of henna <xref ref-type="bibr" rid="ref22">Gupta et al.,1992</xref>. The seeds of Mehndi/Henna contain ~7.5 % viscous oil possessing palmitic, behenic, arachidic, stearic, oleic and linolenic acids <xref ref-type="bibr" rid="ref1">Aggarwal et al., 1959</xref><xref ref-type="bibr" rid="ref25">Handa et al., 1997</xref>. Bioactivity guided fractionation of methanolic seed extract lead to isolation of two new triterpenoids lawnermis acid and its methyl ester <xref ref-type="bibr" rid="ref47">Siddiqui et al., 2005</xref>. The leaves of Mehndi/Henna also contains apigenin-7-glucoside, apigenin-4-glycoside, luteohennan- 7-glucoside luteolin-3-glucoside <xref ref-type="bibr" rid="ref12">Chakrabartty et al., 1982</xref>. The essential oil of Lawsonia inermis seeds contains about 23 components revealed in GC-MS analysis. The principal components were Tridecane (7.7%), phytol (10.30%), Hexadecane (14.88%), Tetradecane (16.77%), Heptadecane (23.48%) <xref ref-type="bibr" rid="ref44">Rahmat et al.,2006</xref>. Structures of the reported anticancer molecules from Lawsonia inermis and some of the derivatives of lawsone is given in <xref ref-type="fig" rid="fig1"> Figure 1 </xref>.</p>
      <fig id="fig1">
        <label>Figure 1</label>
        <caption>
          <title>Reported anticancer molecules from Lawsonia inermis and some derivatives of lawsone</title>
          <p>(A) Lawsone, (B) Luteolin, (C) Apigenin, (D) Fraxetin, (E) Gallic acid, (F) Quercetin, (G) Atovaquone, (H) Lapachol, (I) &#946;-lapachone, (J) Dichloroallyl lawsone.</p>
        </caption>
        <graphic xlink:href="s40730-014-0018-1/fig1.png"/>
      </fig>
    </sec>
    <sec id="s4">
      <title>Anticancer/cytotoxicity activities of lawsonia inermis extract and essential oil</title>
      <p>An assortment of anticancer activities of Lawsonia inermis extracts, essential oil, lawsone and its derivatives have been summarised in <xref ref-type="fig" rid="tab1"> Table 1 </xref> . In addition, description of anticancer studies is provided under the following headings:</p>
      <sec id="s4-1">
        <title>In vitro study on different cancer cell lines</title>
        <p>Discovery of oncogene and apoptotic pathway represents a breakthrough for understanding the molecular and genetic basis of cancer and are considered as one of the most valuable targets for anticancer drug discovery programme, endeavouring the selectivity of new drugs towards cancer cell and sparing the normal ones <xref ref-type="bibr" rid="ref41">Pierotti et al.,2000</xref>. Study conducted on human liver cancer cell line (HepG2) demonstrated induction of the apoptotic phenomena by essential oil and leaves extract of Mehndi/Henna at a concentration of 20 and 30 mg/mL. The induction was evidenced by number of apoptotic bodies, DNA fragmentation and chromatin condensation in the treated groups <xref ref-type="bibr" rid="ref21">Endrini et al., 2011</xref>. Essential oil from the leaves of Mehndi/Henna also exhibited strong cytotoxicity on HepG2 with an IC<sub>50</sub> value of 24&#956;g/mL in MTT assay <xref ref-type="bibr" rid="ref44">Rahmat et al., 2006</xref>. Similarly, in vivo experiment of Roshnah et al., (1998) revealed that Henna reduces chemical-induced hepatocarcinogenesis in rat model. Likewise, chloroform extract of Mehndi leaves showed cytotoxicity on HepG2 and MCF-7 (hormone-dependent breast cancer cell line) with an IC<sub>50</sub> value of 0.3 and 24.8&#956;g/mL respectively. The effect of Mehndi/Henna extract on expression of c-myc gene was also studied and it was observed that the gene was not expressed in cell (HepG2 and MCF-7) treated with 20 and 30&#956;g/mL of crude extract <xref ref-type="bibr" rid="ref20">Endrini et al., 2007</xref>. The expression of the c-myc is indicative of early response during cell proliferation and it has been found to be frequently over expressed in a variety of tissues and cultured cancer cell lines <xref ref-type="bibr" rid="ref45">Saito et al., 1991</xref>. From the study, it was concluded that cytotoxicity was mediated by the down regulation of c-myc expression and it was also observed that the extracts did not exhibit any activity on normal, Caco-2 (colon cancer) and MDA-MB-231 (breast cancer) cell lines <xref ref-type="bibr" rid="ref20">Endrini et al., 2007</xref>.</p>
      </sec>
      <sec id="s4-2">
        <title>In vivo study in different tumour model of rodent</title>
        <p><xref ref-type="bibr" rid="ref40">Ozaslan et al., 2009</xref> explored the effect of Mehndi/Henna powder on cancerous cells and observed that intracellular free radicals and hydrogen peroxide level was escalated but hydrogen ion concentration was reduced which leads to the stimulation of apoptosis as a consequence of oxidative effect. 0.3% aqueous solution prepared and administered to mice for 12 days twice in equal doses resulted in inhibition of Ehrlich Ascites Carcinoma progression with an increase of GSH and SOD level concluding the promotion of apoptosis due to oxidant effect <xref ref-type="bibr" rid="ref40">Ozaslan et al., 2009</xref>. Cancerous cells require more H<sup>+</sup> and intracellular concentration of H<sup>+</sup> in Henna powder treated group was decreased due to its oxidative effect. The ethanolic extract of Mehndi/Henna root connotes anti-tumoral activity in Swiss albino mice at a dose level of 180 mg/kg body weight administered for 15 days in DLA transplanted mice. The body weight, tumor volume, packed cell volume and viable cells were brought back to basal level which was comparable to vincristine (1mg/kg bw), a potent anticancer drug. The experimental finding of the study revealed the reversal of the immunological and pathological abnormalities like increased WBC, platelet, lymphocytes, ALT, AST, ALP, LDH &amp; decreased level of Hb, RBC, PCV, monocytes and differential count in treated mice compared to control group. The hepatocytes of mice treated with Mehndi/Henna and vincristine were well developed with prominent nucleus and maintained sinusoidal space. The findings revealed that ethanolic extract of Mehndi/Henna increased the life span of DLA tumor bearing mice, enhanced the antioxidant status and reduced the lipid profile <xref ref-type="bibr" rid="ref43">Priya et al., 2011</xref>. Modulatory effect of Mehndi/Henna leaf extract on drug metabolising enzymes was investigated by <xref ref-type="bibr" rid="ref19">Dasgupta et al., 2003</xref>. Effect of 200 and 400 mg/kg bw of 80% ethanolic extract of the fresh leaves on drug metabolizing phase I and phase II enzymes, antioxidant enzymes, glutathione content, lactate dehydrogenase and lipid peroxidation in the liver of 7 weeks old Swiss albino mice was investigated. Anti-carcinogenic potential of Mehndi/Henna leaf extract was also studied adopting the protocol of benzo (a) pyrene-induced forestomach and 7, 12 dimethylbenz (a) anthracene (DMBA)-initiated and croton oil-promoted skin papillomagenesis. Outcomes of the primary result reveals the &#8216;duel-acting&#8217; nature of mehndi/henna leaf as only phase II enzyme activity was induced associated with detoxification of carcinogen in liver of mice whereas the activity of phase I enzyme was inhibited. Significant inhibition of tumor burden was observed in both the studied model and reduced tumor incidence was observed in both the doses signifying the cancer chemopreventive potential of mehndi/henna <xref ref-type="bibr" rid="ref19">Dasgupta et al., 2003</xref>.</p>
      </sec>
      <sec id="s4-3">
        <title>Anticancer Activities of Lawsone and Its Derivatives</title>
        <p>Lawsone (2-hydroxy-1, 4-naphthoquinone) a key molecules of mehndi/henna is being used as starting material in the synthesis of variety of clinically valuable anticancer drugs such as Atovaquone, Lapachol and Dichloroallyl lawsone <xref ref-type="bibr" rid="ref42">Pradhan et al., 2012</xref>. Lawsone and juglone inhibit the growth of HCT-15 (human colon cancer cells) by blocking the S-phase of cell cycle observed during flow cytometric study. Furano-1, 2- naphthoquinone synthesised from 2- hydroxy-1, 4-naphthoquinone and chloroacetaldehyde, blocked the growth of A549 (lung cancer cells) by mediating G(2)/M cell cycle arrest and promoting apoptosis <xref ref-type="bibr" rid="ref28">Kamei et al., 1998</xref>. Induction of the apoptosis was escorted by upregulation of Bax and down-regulation of Bcl-2. In addition, the compound also affected EGFR phosphorylation, JAK2, STAT3, and STAT5 activation, and brings about activation of p38 MAPK and c-Jun NH2-terminal kinase (JNK) stress signals <xref ref-type="bibr" rid="ref48">Su et al., 2010</xref>. In another study on Furano-1, 2- naphthoquinone, <xref ref-type="bibr" rid="ref14">Chien and Co-worker, 2010</xref> reported suppression of EGF receptor phosphorylation and activation of PI3K/Akt in Ca9-22 (oral cancer cells). Interrupted mitochondrial membrane potential, release of cytochrome C, activation of caspases 3 and 9 fetched apoptosis in Ca9-22 cells via inactivation of the EGF receptor <xref ref-type="bibr" rid="ref14">Chien et al., 2010</xref>.</p>
        <p>Amino-derivatives of lawsone and lapachol were found to be cytotoxic against Ehrlich carcinoma and human K562 (leukemia cells). Allyl-amine derivatives of lawsone and lapachol were found potent cytotoxic with an IC<sub>50</sub> values of 23.89 and 16.94 &#956;M respectively <xref ref-type="bibr" rid="ref17">da Silva et al., 2002</xref>. Dichloroallyl lawsone, an analog of the lapachol, and acivicin inhibit the biosynthesis of nucleotide and showed anticancer activity against certain experimental tumor models <xref ref-type="bibr" rid="ref30">Kemp et al., 1986</xref>. Dichloroallyl lawsone is an important chemotherapeutic agent causes cardiac toxicity in the rhesus monkey <xref ref-type="bibr" rid="ref36">McKelvey et al., 1979</xref>.</p>
      </sec>
      <sec id="s4-4">
        <title>Chemopreventive Properties in Skin Cancer</title>
        <p>Mehndi/Henna leaf powder and lawsone significantly exhibited inhibition (&gt;88%) of EBV-EA activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells (human cell line from hematopoietic origin, produces an unusual strain of Epstein-Barr virus which transforms cord blood lymphocytes and induce early antigens). In two-stage mouse skin carcinogenesis model, tumour incidence was decreased by 66% and multiplicity by 40% in Mehndi/Henna powder treatment and decreased tumour incidence by 72% and multiplicity by 50% were reported using UV-B radiation for initiation and TPA for tumour promotion. The tumour inhibitory tendency was sustained during the 20-week test period. Similar antitumor activities were observed when Mehndi/Henna (0.5 mg/ml) and lawsone (0.015 mg/ml) were applied topically on the back skin in the UV-B initiated/TPA promoted and peroxynitrite initiated/TPA promoted mouse skin carcinogenesis models <xref ref-type="bibr" rid="ref29">Kapadia et al.,2013</xref>.</p>
      </sec>
      <fig id="tab1">
        <label>Table 1</label>
        <caption>
          <p>Table 1</p>
        </caption>
        <graphic xlink:href="s40730-014-0018-1/tab1.png"/>
      </fig>
    </sec>
    <sec id="s5">
      <title>A Case Study</title>
      <p>Hand Foot Syndrome (HFS), the most frequent cutaneous adverse effect of capecitabine (a prodrug of 5-Florouracil) is manifested as acral erythema with swelling and dysesthesia of the palms and soles. It interferes significantly with normal daily activities of patients undergoing treatment with capecitabine. A breast cancer patient undergoing capecitabine treatment at the Department of Medical Oncology, Ondokuz Mayis University Medical School, Turkey complained about the presence of skin rashes on her feet but not in hands. Later she was diagnosed with HFS and it was observed that she had applied mehndi/henna on her hands which was an exciting case for the researchers. Following it as an example case, six patients with severe case of HFS were recommended to apply mehndi/henna on their hands. Astoundingly, after using mehndi/henna, whinges were reduced in 48 h and disappeared in one week <xref ref-type="bibr" rid="ref52">Yucel and Guzin, 2008</xref>.</p>
    </sec>
    <sec id="s6">
      <title>Conclusions</title>
      <p>Despite being used as a cosmetic agent in the Oriental regions of the world to dye hair and in body art, Mehndi/Henna holds several cytotoxic and chemopreventive agents in its possession. The present review recapitulates some important findings on the anticancer potential of Mehndi/Henna and to a great extent more work needs to be embark on to explore its novel target(s). Phytochemistry of Mehndi/Henna needs a broader study for the isolation of novel compounds and pharmacological studies on suitable models and clinically established cancer biomarkers will help to identify pioneering chemotherapeutic and/or chemopreventive agent. Future investigation on these aspects of Mehndi/Henna may offer great hope for the discovery of new anticancer agents from this miraculous plant.</p>
    </sec>
    <sec id="s7">
      <title>Abbreviations</title>
      <p>AYUSH: Ayurveda, Yoga &amp; Naturopathy, Unani, Sidha and Homeopathy Medicine; IC<sub>50</sub>- 50 percent inhibitory concentration; GSH: Glutathione; SOD: Superoxide dismutase; DLA: Dalton lymphoma ascitis; WBC: White blood cells; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatise; LDH: Lactate dehydrogenase; Hb: Haemoglobin; RBC: Red blood cells; PCV: Packed cell volume; PON: Peroxynitrile.</p>
    </sec>
  </body>
  <back>
    <ack id="ack">
      <title>Acknowledgements</title>
      <p>Authors are grateful to Council of Scientific and Industrial Research (CSIR), New Delhi, India for CSIR-GATE-JRF to DKS and Network Project Funding at CSIR-CIMAP, Lucknow (XII FYP Networking Project BSC 0121). Research work on plant based drug discovery in our laboratory is also supported by Science and Engineering Research Board, Department of Science and Technology, Ministry of Science and Technology, Government of India.</p>
    </ack>
    <ref-list>
      <title>References</title>
      <ref id="ref1">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>S.R. S.N. G.</surname>
              <given-names>Aggarwal</given-names>
            </name>
            <name>
              <surname>D.R.</surname>
              <given-names>Dhingra</given-names>
            </name>
          </person-group>
          <article-title>Chemical examination of the seed oil of Lawsonia alba</article-title>
          <source>Indian Oil Soap Journal.</source>
          <year>1959</year>
          <volume>145</volume>
        </element-citation>
      </ref>
      <ref id="ref2">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>M.</surname>
              <given-names>Al-Tufail</given-names>
            </name>
            <name>
              <surname>P.</surname>
              <given-names>Krahn</given-names>
            </name>
            <name>
              <surname>H.</surname>
              <given-names>Hassan</given-names>
            </name>
            <name>
              <surname>T.</surname>
              <given-names>Mahier</given-names>
            </name>
            <name>
              <surname>S.T.</surname>
              <given-names>Al-Sedairy</given-names>
            </name>
            <name>
              <surname>A.</surname>
              <given-names>Haq</given-names>
            </name>
          </person-group>
          <article-title>Rapid identification of ph enylenediamine isomers in henna hair dye products by gas chromatography-mass spectrometry (GC- MS)</article-title>
          <source>Toxicological &amp; Environmental Chemistry</source>
          <year>1999</year>
          <fpage>241</fpage>
          <lpage>246</lpage>
        </element-citation>
      </ref>
      <ref id="ref3">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>B.H.</surname>
              <given-names>Ali</given-names>
            </name>
            <name>
              <surname>A.K.</surname>
              <given-names>Bashir</given-names>
            </name>
            <name>
              <surname>M.O.</surname>
              <given-names>Tanira</given-names>
            </name>
          </person-group>
          <article-title>Anti-inflammatory, antipyretic, and analgesic effects of Lawsonia inermis L. (henna) in rats.</article-title>
          <source>Pharmacology</source>
          <year>1995</year>
          <volume>51</volume>
          <fpage>356</fpage>
          <lpage>363</lpage>
        </element-citation>
      </ref>
      <ref id="ref4">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>M.</surname>
              <given-names>Ali</given-names>
            </name>
            <name>
              <surname>M.R.</surname>
              <given-names>Grever</given-names>
            </name>
          </person-group>
          <article-title>A cytotoxic naphthoquinone from Lawsonia inermis</article-title>
          <source>Fitoterapia</source>
          <year>1998</year>
          <fpage>1810</fpage>
          <lpage>181369</lpage>
        </element-citation>
      </ref>
      <ref id="ref5">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>K.K.</surname>
              <given-names>Anand</given-names>
            </name>
            <name>
              <surname>B.</surname>
              <given-names>Singh</given-names>
            </name>
            <name>
              <surname>D.</surname>
              <given-names>Chand</given-names>
            </name>
            <name>
              <surname>B.K.</surname>
              <given-names>Chandan</given-names>
            </name>
          </person-group>
          <article-title>An evaluation of Lawsonia alba extract as hepatoprotective agent</article-title>
          <source>Planta medica</source>
          <year>1992</year>
          <volume>58</volume>
          <fpage>22</fpage>
          <lpage>25</lpage>
        </element-citation>
      </ref>
      <ref id="ref6">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>F.E.</surname>
              <given-names>Babili</given-names>
            </name>
            <name>
              <surname>J.</surname>
              <given-names>Bouajila</given-names>
            </name>
            <name>
              <surname>A.</surname>
              <given-names>Valentin</given-names>
            </name>
            <name>
              <surname>C.</surname>
              <given-names>Chatelain</given-names>
            </name>
          </person-group>
          <article-title>Lawsonia Inermis: Its Anatomy and its Antimalarial, Antioxidant and Human Breast Cancer Cells MCF7 Activities</article-title>
          <source>Pharmaceut Anal Acta</source>
          <year>2013</year>
          <fpage>203</fpage>
        </element-citation>
      </ref>
      <ref id="ref7">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>I.T.</surname>
              <given-names>Balassiano</given-names>
            </name>
            <name>
              <surname>S.A.</surname>
              <given-names>De Paulo</given-names>
            </name>
            <name>
              <surname>N.</surname>
              <given-names>Henriques Silva</given-names>
            </name>
            <name>
              <surname>M.C.</surname>
              <given-names>Cabral</given-names>
            </name>
            <name>
              <surname>M.</surname>
              <given-names>da Gloria da Costa Carvalho</given-names>
            </name>
          </person-group>
          <article-title>Demonstration of the lapachol as a potential drug for reducing cancer metastasis</article-title>
          <source>Oncology reports</source>
          <year>2005</year>
          <volume>13</volume>
          <fpage>329</fpage>
          <lpage>333</lpage>
        </element-citation>
      </ref>
      <ref id="ref8">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>D.K.</surname>
              <given-names>Bhardwaj</given-names>
            </name>
            <name>
              <surname>M.S. K. J.R.</surname>
              <given-names>Bisht</given-names>
            </name>
          </person-group>
          <article-title>Constituents of laxanthones II: Synthetic studies</article-title>
          <source>Proceeding of Indian National Science Academy</source>
          <year>1980</year>
          <fpage>381</fpage>
          <lpage>386</lpage>
        </element-citation>
      </ref>
      <ref id="ref9">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>D.K.</surname>
              <given-names>Bhardwaj</given-names>
            </name>
            <name>
              <surname>R.K.</surname>
              <given-names>Jain</given-names>
            </name>
            <name>
              <surname>B.C.</surname>
              <given-names>Jain</given-names>
            </name>
            <name>
              <surname>C.K.</surname>
              <given-names>Mehta</given-names>
            </name>
          </person-group>
          <article-title>1- hydroxy-3, 7-dimethoxy-6-acetoxy xanthone a new xanthone from Lawsonia inermis</article-title>
          <source>Phytochemistry</source>
          <year>1978</year>
          <fpage>1440</fpage>
          <lpage>1441</lpage>
        </element-citation>
      </ref>
      <ref id="ref10">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>J.C.</surname>
              <given-names>Cartwright</given-names>
            </name>
          </person-group>
          <article-title>Developing guidelines on henna: a geographical approach</article-title>
          <source>Tap Dancing Lizard Publishing</source>
          <year>2006</year>
        </element-citation>
      </ref>
      <ref id="ref11">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>J.M.</surname>
              <given-names>Cassady</given-names>
            </name>
            <name>
              <surname>J.D.</surname>
              <given-names>Douros</given-names>
            </name>
          </person-group>
          <article-title>Anticancer Agents Based on Natural Product Models</article-title>
          <source>Academic Press</source>
          <year>1980</year>
        </element-citation>
      </ref>
      <ref id="ref12">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>T.</surname>
              <given-names>Chakrabartty</given-names>
            </name>
            <name>
              <surname>G.</surname>
              <given-names>Poddar</given-names>
            </name>
            <name>
              <surname>J.</surname>
              <given-names>St. Pyrek</given-names>
            </name>
          </person-group>
          <article-title>Isolation of dihydroxy lupene and dihydroxy lupane from the bark of Lawsonia inermis</article-title>
          <source>Phytochemistry</source>
          <year>1982</year>
          <fpage>1814</fpage>
          <lpage>1816</lpage>
        </element-citation>
      </ref>
      <ref id="ref13">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>T. G. P.</surname>
              <given-names>Chakrabortty</given-names>
            </name>
            <name>
              <surname>S.K.</surname>
              <given-names>Deshmukh</given-names>
            </name>
          </person-group>
          <article-title>Triterpenoids and other constituents of Lawsonia inermis</article-title>
          <source>Indian Journal of Chemistry</source>
          <year>1980</year>
          <fpage>96&#173;97</fpage>
        </element-citation>
      </ref>
      <ref id="ref14">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>C.M.</surname>
              <given-names>Chien</given-names>
            </name>
            <name>
              <surname>K.L.</surname>
              <given-names>Lin</given-names>
            </name>
            <name>
              <surname>J.C.</surname>
              <given-names>Su</given-names>
            </name>
            <name>
              <surname>P.W.</surname>
              <given-names>Chuang</given-names>
            </name>
            <name>
              <surname>C.H.</surname>
              <given-names>Tseng</given-names>
            </name>
            <name>
              <surname>Y.L.</surname>
              <given-names>Chen</given-names>
            </name>
            <name>
              <surname>L.S.</surname>
              <given-names>Chang</given-names>
            </name>
            <name>
              <surname>S.R.</surname>
              <given-names>Lin</given-names>
            </name>
          </person-group>
          <article-title>Naphtho[1,2-b]furan-4,5-dione induces apoptosis of oral squamous cell carcinoma: involvement of EGF receptor/PI3K/Akt signaling pathway</article-title>
          <source>European journal of pharmacology</source>
          <year>2010</year>
          <volume>636</volume>
          <fpage>52</fpage>
          <lpage>58</lpage>
        </element-citation>
      </ref>
      <ref id="ref15">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>G.M.</surname>
              <given-names>Cragg</given-names>
            </name>
            <name>
              <surname>D.J.</surname>
              <given-names>Newman</given-names>
            </name>
          </person-group>
          <article-title>Plants as a source of anti-cancer agents</article-title>
          <source>Journal of ethnopharmacology</source>
          <year>2005</year>
          <volume>100</volume>
          <fpage>72</fpage>
          <lpage>79</lpage>
        </element-citation>
      </ref>
      <ref id="ref16">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>G.M.</surname>
              <given-names>Cragg</given-names>
            </name>
            <name>
              <surname>D.J.</surname>
              <given-names>Newman</given-names>
            </name>
            <name>
              <surname>K.M.</surname>
              <given-names>Snader</given-names>
            </name>
          </person-group>
          <article-title>Natural products in drug discovery and development</article-title>
          <source>Journal of natural products</source>
          <year>1997</year>
          <volume>60</volume>
          <fpage>52&#173;60</fpage>
        </element-citation>
      </ref>
      <ref id="ref17">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>A.J.</surname>
              <given-names>Silva</given-names>
            </name>
            <name>
              <surname>C.D.</surname>
              <given-names>Buarque</given-names>
            </name>
            <name>
              <surname>F.V.</surname>
              <given-names>Brito</given-names>
            </name>
            <name>
              <surname>L.</surname>
              <given-names>Aurelian</given-names>
            </name>
            <name>
              <surname>L.F.</surname>
              <given-names>Macedo</given-names>
            </name>
            <name>
              <surname>L.H.</surname>
              <given-names>Malkas</given-names>
            </name>
            <name>
              <surname>R.J.</surname>
              <given-names>Hickey</given-names>
            </name>
            <name>
              <surname>D.V.</surname>
              <given-names>Lopes</given-names>
            </name>
            <name>
              <surname>F.</surname>
              <given-names>Noel</given-names>
            </name>
            <name>
              <surname>Y.L</surname>
              <given-names>Murakami</given-names>
            </name>
          </person-group>
          <article-title>Synthesis and preliminary pharmacological evaluation of new (+/-) 1,4-naphthoquinones structurally related to lapachol</article-title>
          <source>Bioorganic &amp; medicinal chemistry</source>
          <year>2002</year>
          <volume>10</volume>
          <fpage>2731</fpage>
          <lpage>2738</lpage>
        </element-citation>
      </ref>
      <ref id="ref18">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>S.A. A. K.R.</surname>
              <given-names>Dahanukar</given-names>
            </name>
            <name>
              <surname>N.N.</surname>
              <given-names>Rege</given-names>
            </name>
          </person-group>
          <article-title>Pharmacology of medic-inal plants and natural products</article-title>
          <source>Indian Journal of Pharmacology</source>
          <year>2000</year>
          <fpage>81</fpage>
          <lpage>118</lpage>
        </element-citation>
      </ref>
      <ref id="ref19">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>T.</surname>
              <given-names>Dasgupta</given-names>
            </name>
            <name>
              <surname>A.R.</surname>
              <given-names>Rao</given-names>
            </name>
            <name>
              <surname>P.K.</surname>
              <given-names>Yadava</given-names>
            </name>
          </person-group>
          <article-title>Modulatory effect of henna leaf (Lawsonia inermis) on drug metabolising phase I and phase II enzymes, antioxidant enzymes, lipid peroxidation and chemically induced skin and fore stomach papillom agenesis in mice</article-title>
          <source>Molecular and cellular biochemistry</source>
          <year>2003</year>
          <volume>245</volume>
          <fpage>11</fpage>
          <lpage>22</lpage>
        </element-citation>
      </ref>
      <ref id="ref20">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>S.</surname>
              <given-names>Endrini</given-names>
            </name>
            <name>
              <surname>A.</surname>
              <given-names>Rahmat</given-names>
            </name>
            <name>
              <surname>P.</surname>
              <given-names>Ismail</given-names>
            </name>
            <name>
              <surname>Y.H.</surname>
              <given-names>Taufiq-Yap</given-names>
            </name>
          </person-group>
          <article-title>Comparing of the Cytotoxicity Properties and Mechanism of Lawsonia inermis and Strobilanthes crispus extract against several cancer cell lines</article-title>
          <source>Journal of Medical Sciences</source>
          <year>2007</year>
          <fpage>1098</fpage>
          <lpage>1102</lpage>
        </element-citation>
      </ref>
      <ref id="ref21">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>S.</surname>
              <given-names>Endrini</given-names>
            </name>
            <name>
              <surname>A.</surname>
              <given-names>Rahmat</given-names>
            </name>
            <name>
              <surname>P.</surname>
              <given-names>Ismail</given-names>
            </name>
            <name>
              <surname>Y.H. F. O.</surname>
              <given-names>Taufiq-Yap</given-names>
            </name>
          </person-group>
          <article-title>Effects of Henna (Lawsonia inermis) on the Apoptotic Pathway of Human liver Carci-noma Cell lines</article-title>
          <source>Journal of Applied Sciences Research</source>
          <year>2011</year>
          <fpage>321</fpage>
          <lpage>326</lpage>
        </element-citation>
      </ref>
      <ref id="ref22">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>S.</surname>
              <given-names>Gupta</given-names>
            </name>
            <name>
              <surname>M.</surname>
              <given-names>Ahenna</given-names>
            </name>
            <name>
              <surname>M.S.</surname>
              <given-names>Alam</given-names>
            </name>
            <name>
              <surname>M.</surname>
              <given-names>Niwa</given-names>
            </name>
            <name>
              <surname>T.</surname>
              <given-names>Sakai</given-names>
            </name>
          </person-group>
          <article-title>199224-beta ethylcholest-4-en-3-beta-ol from the Roots of Lawsonia inermis</article-title>
          <source>Phytochemistry</source>
          <year>1992</year>
          <fpage>2558</fpage>
          <lpage>2560</lpage>
        </element-citation>
      </ref>
      <ref id="ref23">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>S.</surname>
              <given-names>Gupta</given-names>
            </name>
            <name>
              <surname>M.</surname>
              <given-names>Ahenna</given-names>
            </name>
            <name>
              <surname>M.S.</surname>
              <given-names>Alam</given-names>
            </name>
            <name>
              <surname>T.</surname>
              <given-names>Sakae</given-names>
            </name>
            <name>
              <surname>M.</surname>
              <given-names>Niwa</given-names>
            </name>
          </person-group>
          <article-title>A new aliphatic hydrocarbon from Lawsonia inermis bark</article-title>
          <source>Indian Journal of Chemistry</source>
          <year>1992</year>
          <fpage>705</fpage>
          <lpage>707</lpage>
        </element-citation>
      </ref>
      <ref id="ref24">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>S.</surname>
              <given-names>Gupta</given-names>
            </name>
            <name>
              <surname>M.</surname>
              <given-names>Ali</given-names>
            </name>
            <name>
              <surname>M.S.</surname>
              <given-names>Alam</given-names>
            </name>
          </person-group>
          <article-title>A napthoquinone from Lawsonia inermis stem bark</article-title>
          <source>Phytochemistry</source>
          <year>1993</year>
          <fpage>723</fpage>
          <lpage>724</lpage>
        </element-citation>
      </ref>
      <ref id="ref25">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>G.</surname>
              <given-names>Handa</given-names>
            </name>
            <name>
              <surname>A.</surname>
              <given-names>Kapil</given-names>
            </name>
            <name>
              <surname>S.</surname>
              <given-names>Sharma</given-names>
            </name>
            <name>
              <surname>J.</surname>
              <given-names>Singh</given-names>
            </name>
          </person-group>
          <article-title>Lawnermis acid a new anti-complementary tri-terpenoids from Lawsonia inermis seeds</article-title>
          <source>Indian Journal of Chemistry</source>
          <year>1997</year>
          <fpage>252</fpage>
          <lpage>256</lpage>
        </element-citation>
      </ref>
      <ref id="ref26">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>R. N. M.J.</surname>
              <given-names>Hanna</given-names>
            </name>
            <name>
              <surname>L.</surname>
              <given-names>Lapinsky</given-names>
            </name>
            <name>
              <surname>L.</surname>
              <given-names>Adamowicz</given-names>
            </name>
          </person-group>
          <article-title>Molecular struc-ture and infra red spectra of 2-hydroxyl, 4- naphthaquinone: Experimental matrix isolation and theoretical</article-title>
          <source>Spectrochimica Acta</source>
          <year>1998</year>
          <fpage>1091</fpage>
          <lpage>1103</lpage>
        </element-citation>
      </ref>
      <ref id="ref27">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>B.A.</surname>
              <given-names>H so una</given-names>
            </name>
            <name>
              <surname>M.G.</surname>
              <given-names>Culioli</given-names>
            </name>
            <name>
              <surname>Y.</surname>
              <given-names>Blache</given-names>
            </name>
            <name>
              <surname>S.</surname>
              <given-names>Jaoua</given-names>
            </name>
          </person-group>
          <article-title>Antioxidant constitu-ents from lawsonia inermis leaves: isolation, structure elucidation and antioxidative capacity</article-title>
          <source>Food Chemistry</source>
          <year>2010</year>
          <fpage>193&#173;200</fpage>
        </element-citation>
      </ref>
      <ref id="ref28">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>H.</surname>
              <given-names>Kamei</given-names>
            </name>
            <name>
              <surname>T.</surname>
              <given-names>Koide</given-names>
            </name>
            <name>
              <surname>T.</surname>
              <given-names>Kojima</given-names>
            </name>
            <name>
              <surname>Y.</surname>
              <given-names>Hashimoto</given-names>
            </name>
            <name>
              <surname>M.</surname>
              <given-names>Hasegawa</given-names>
            </name>
          </person-group>
          <article-title>Inhibition of cell growth in culture by quinones</article-title>
          <source>Cancer biotherapy &amp; radiopharmaceuticals</source>
          <year>1998</year>
          <volume>13</volume>
          <fpage>185</fpage>
          <lpage>188</lpage>
        </element-citation>
      </ref>
      <ref id="ref29">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>G.J.</surname>
              <given-names>Kapadia</given-names>
            </name>
            <name>
              <surname>G.S.</surname>
              <given-names>Rao</given-names>
            </name>
            <name>
              <surname>R.</surname>
              <given-names>Sridhar</given-names>
            </name>
            <name>
              <surname>E.</surname>
              <given-names>Ichiishi</given-names>
            </name>
            <name>
              <surname>M.</surname>
              <given-names>Takasaki</given-names>
            </name>
            <name>
              <surname>N.</surname>
              <given-names>Suzuki</given-names>
            </name>
            <name>
              <surname>T.</surname>
              <given-names>Konoshima</given-names>
            </name>
            <name>
              <surname>A.</surname>
              <given-names>Iida</given-names>
            </name>
            <name>
              <surname>H.</surname>
              <given-names>Tokuda</given-names>
            </name>
          </person-group>
          <article-title>Chemoprevention of skin cancer: effect of Lawsonia inermis L. (Henna) leaf powder and its pigment artifact, lawsone in the Epstein- Barr virus early antigen activation assay and in two-stage mouse skin carcinogenesis models</article-title>
          <source>Anti&#173;cancer agents in medicinal chemistry</source>
          <year>2013</year>
          <volume>13</volume>
          <fpage>1500</fpage>
          <lpage>1507</lpage>
        </element-citation>
      </ref>
      <ref id="ref30">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>A.J.</surname>
              <given-names>Kemp</given-names>
            </name>
            <name>
              <surname>S.D.</surname>
              <given-names>Lyons</given-names>
            </name>
            <name>
              <surname>R.I.</surname>
              <given-names>Christopher son</given-names>
            </name>
          </person-group>
          <article-title>Effects of acivicin and dichloroallyl lawsone upon pyrimidine biosynthesis in mouse L1210 leukemia cells</article-title>
          <source>The Journal of biological chemistry</source>
          <year>1986</year>
          <volume>261</volume>
          <fpage>14891&#173;14895</fpage>
        </element-citation>
      </ref>
      <ref id="ref31">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Z.S. S. N.</surname>
              <given-names>Khan</given-names>
            </name>
          </person-group>
          <article-title>Phytochemical analysis, antifungal activity and mode of action of methanol extracts from plants against pathogens</article-title>
          <source>Journal of Agricultural Technology</source>
          <year>2010</year>
          <fpage>793</fpage>
          <lpage>805</lpage>
        </element-citation>
      </ref>
      <ref id="ref32">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>K.R.</surname>
              <given-names>Kirtikar</given-names>
            </name>
            <name>
              <surname>B.D.</surname>
              <given-names>Basu</given-names>
            </name>
          </person-group>
          <article-title>Indian Medicinal Plants, 2nd edn</article-title>
          <source>International book distributors</source>
          <year>2005</year>
        </element-citation>
      </ref>
      <ref id="ref33">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>N.</surname>
              <given-names>Lekouch</given-names>
            </name>
            <name>
              <surname>A.</surname>
              <given-names>Sedki</given-names>
            </name>
            <name>
              <surname>A. S. G.</surname>
              <given-names>Nejmeddine</given-names>
            </name>
          </person-group>
          <article-title>Lead and traditional Moroccan pharmacopoein</article-title>
          <source>The Science of the Total En vironment</source>
          <year>2001</year>
          <fpage>39</fpage>
          <lpage>34</lpage>
        </element-citation>
      </ref>
      <ref id="ref34">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>F.</surname>
              <given-names>Malekzadeh</given-names>
            </name>
          </person-group>
          <article-title>Antimicrobial activity of Lawsonia inermis L</article-title>
          <source>Applied microbiology</source>
          <year>1968</year>
          <volume>16</volume>
          <fpage>663</fpage>
          <lpage>664</lpage>
        </element-citation>
      </ref>
      <ref id="ref35">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>M.</surname>
              <given-names>McClellan</given-names>
            </name>
            <name>
              <surname>J.</surname>
              <given-names>Benner</given-names>
            </name>
            <name>
              <surname>R.</surname>
              <given-names>Schilsky</given-names>
            </name>
            <name>
              <surname>D.</surname>
              <given-names>Epstein</given-names>
            </name>
            <name>
              <surname>R.</surname>
              <given-names>Woosley</given-names>
            </name>
            <name>
              <surname>S.</surname>
              <given-names>Friend</given-names>
            </name>
            <name>
              <surname>D.</surname>
              <given-names>Sidransky</given-names>
            </name>
            <name>
              <surname>C.</surname>
              <given-names>Geoghegan</given-names>
            </name>
            <name>
              <surname>D.</surname>
              <given-names>Kessler</given-names>
            </name>
          </person-group>
          <article-title>An accelerated pathway for targeted cancer therapies</article-title>
          <source>Nature reviews Drug discovery</source>
          <year>2011</year>
          <volume>10</volume>
          <fpage>79</fpage>
          <lpage>80</lpage>
        </element-citation>
      </ref>
      <ref id="ref36">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>E.M.</surname>
              <given-names>McKelvey</given-names>
            </name>
            <name>
              <surname>M.</surname>
              <given-names>Lomedico</given-names>
            </name>
            <name>
              <surname>K.</surname>
              <given-names>Lu</given-names>
            </name>
            <name>
              <surname>M.</surname>
              <given-names>Chadwick</given-names>
            </name>
            <name>
              <surname>T.L.</surname>
              <given-names>Loo</given-names>
            </name>
          </person-group>
          <article-title>Dichloroallyl lawsone</article-title>
          <source>Clinical pharmacology and therapeutics</source>
          <year>1979</year>
          <volume>25</volume>
          <fpage>586</fpage>
          <lpage>590</lpage>
        </element-citation>
      </ref>
      <ref id="ref37">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>B.R.</surname>
              <given-names>Mikhaeil</given-names>
            </name>
            <name>
              <surname>F.A.</surname>
              <given-names>Badria</given-names>
            </name>
            <name>
              <surname>G.T.</surname>
              <given-names>Maatooq</given-names>
            </name>
            <name>
              <surname>M.M.</surname>
              <given-names>Amer</given-names>
            </name>
          </person-group>
          <article-title>Antioxidant and immunomodulatory constituents of henna leaves</article-title>
          <source>Z Naturforsch</source>
          <year>2004</year>
          <fpage>468</fpage>
          <lpage>476</lpage>
        </element-citation>
      </ref>
      <ref id="ref38">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>B.S.</surname>
              <given-names>Nayak</given-names>
            </name>
            <name>
              <surname>G.</surname>
              <given-names>Isitor</given-names>
            </name>
            <name>
              <surname>E.M.</surname>
              <given-names>Davis</given-names>
            </name>
            <name>
              <surname>G.K.</surname>
              <given-names>Pillai</given-names>
            </name>
          </person-group>
          <article-title>The evidence based wound healing activity of Lawsonia inermis Linn</article-title>
          <source>Phytotherapy research : PTR</source>
          <year>2007</year>
          <volume>21</volume>
          <fpage>827</fpage>
          <lpage>831</lpage>
        </element-citation>
      </ref>
      <ref id="ref39">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>C.Y.</surname>
              <given-names>Ong</given-names>
            </name>
            <name>
              <surname>S.K.</surname>
              <given-names>Ling</given-names>
            </name>
            <name>
              <surname>R.M.</surname>
              <given-names>Ali</given-names>
            </name>
            <name>
              <surname>C.F.</surname>
              <given-names>Chee</given-names>
            </name>
            <name>
              <surname>Z.A.</surname>
              <given-names>Samah</given-names>
            </name>
            <name>
              <surname>A.S.</surname>
              <given-names>Ho</given-names>
            </name>
            <name>
              <surname>S.H.</surname>
              <given-names>Teo</given-names>
            </name>
            <name>
              <surname>H.B.</surname>
              <given-names>Lee</given-names>
            </name>
          </person-group>
          <article-title>Systematic analysis of in vitro photo- cytotoxic activity in extracts from terrestrial plants in Peninsula Malaysia for photodynamic therapy</article-title>
          <source>Journal of photochemistry and photobiology</source>
          <year>2009</year>
          <volume>B</volume>
          <fpage>Biology 96, 216</fpage>
          <lpage>222</lpage>
        </element-citation>
      </ref>
      <ref id="ref40">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>M.</surname>
              <given-names>Ozaslan</given-names>
            </name>
            <name>
              <surname>M.E.</surname>
              <given-names>Zumrutdal</given-names>
            </name>
            <name>
              <surname>K.</surname>
              <given-names>Daglioglu</given-names>
            </name>
            <name>
              <surname>I.H.</surname>
              <given-names>Kilic</given-names>
            </name>
            <name>
              <surname>I.D.</surname>
              <given-names>Karagoz</given-names>
            </name>
          </person-group>
          <article-title>Antitumoral effect of L. inermis in mice with EAC</article-title>
          <source>InternationalJournal of Pharmacology</source>
          <year>2009</year>
          <fpage>263</fpage>
          <lpage>267</lpage>
        </element-citation>
      </ref>
      <ref id="ref41">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>M.A.</surname>
              <given-names>Pierotti</given-names>
            </name>
            <name>
              <surname>S.A.</surname>
              <given-names>Schichman</given-names>
            </name>
            <name>
              <surname>G.</surname>
              <given-names>Sozzi</given-names>
            </name>
            <name>
              <surname>C.M.</surname>
              <given-names>Croce</given-names>
            </name>
          </person-group>
          <article-title>Oncogenes</article-title>
          <source>In Cancer Medicine, R.C. Bast , ed. (Hamilton: B.C Decker)</source>
          <year>2000</year>
          <fpage>56</fpage>
          <lpage>66</lpage>
        </element-citation>
      </ref>
      <ref id="ref42">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>R.</surname>
              <given-names>Pradhan</given-names>
            </name>
            <name>
              <surname>P.</surname>
              <given-names>Dandawate</given-names>
            </name>
            <name>
              <surname>A.</surname>
              <given-names>Vyas</given-names>
            </name>
            <name>
              <surname>S.</surname>
              <given-names>Padhye</given-names>
            </name>
            <name>
              <surname>B.</surname>
              <given-names>Biersack</given-names>
            </name>
            <name>
              <surname>R.</surname>
              <given-names>Schobert</given-names>
            </name>
            <name>
              <surname>A.</surname>
              <given-names>Ahmad</given-names>
            </name>
            <name>
              <surname>F.H.</surname>
              <given-names>Sarkar</given-names>
            </name>
          </person-group>
          <article-title>From body art to anticancer activities: perspectives on medicinal properties of henna</article-title>
          <source>Current drug targets</source>
          <year>2012</year>
          <volume>13</volume>
          <fpage>1777</fpage>
          <lpage>1798</lpage>
        </element-citation>
      </ref>
      <ref id="ref43">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>R.</surname>
              <given-names>Priya</given-names>
            </name>
            <name>
              <surname>S.</surname>
              <given-names>Ilavenil</given-names>
            </name>
            <name>
              <surname>B.</surname>
              <given-names>Kaleeswaran</given-names>
            </name>
            <name>
              <surname>S.</surname>
              <given-names>Srigopalram</given-names>
            </name>
            <name>
              <surname>S.</surname>
              <given-names>Ravikumar</given-names>
            </name>
          </person-group>
          <article-title>Effect of Lawsonia inermis on tumor expression induced by Dalton's lymphoma ascites in Swiss albino mice</article-title>
          <source>Saudi journal of biological sciences</source>
          <year>2011</year>
          <volume>18</volume>
          <fpage>353</fpage>
          <lpage>359</lpage>
        </element-citation>
      </ref>
      <ref id="ref44">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>A.</surname>
              <given-names>Rahmat</given-names>
            </name>
            <name>
              <surname>S.</surname>
              <given-names>Edrini</given-names>
            </name>
            <name>
              <surname>P.</surname>
              <given-names>Ismail</given-names>
            </name>
            <name>
              <surname>T.</surname>
              <given-names>Yap</given-names>
            </name>
            <name>
              <surname>Y.</surname>
              <given-names>Hin</given-names>
            </name>
            <name>
              <surname>M.F.A.</surname>
              <given-names>Bakar</given-names>
            </name>
          </person-group>
          <article-title>Chemical Constituents, Antioxidant Activity and Cytotoxic Effects of Essential Oil from Strobilanthes crispus and Lawsonia inermis</article-title>
          <source>Journal of Biological Sciences</source>
          <year>2006</year>
          <fpage>1005</fpage>
          <lpage>1010</lpage>
        </element-citation>
      </ref>
      <ref id="ref45">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>H.</surname>
              <given-names>Saito</given-names>
            </name>
            <name>
              <surname>T.</surname>
              <given-names>Morizane</given-names>
            </name>
            <name>
              <surname>T.</surname>
              <given-names>Watanabe</given-names>
            </name>
            <name>
              <surname>T.</surname>
              <given-names>Kagawa</given-names>
            </name>
            <name>
              <surname>S.</surname>
              <given-names>Miyaguchi</given-names>
            </name>
            <name>
              <surname>N.</surname>
              <given-names>Kumagai</given-names>
            </name>
            <name>
              <surname>M.</surname>
              <given-names>Tsuchiya</given-names>
            </name>
          </person-group>
          <article-title>Differentiating effect of sodium butyrate on human hepatoma cell lines PLC/PRF/5, HCC-M and HCC- T</article-title>
          <source>International journal of cancer Journal international du cancer</source>
          <year>1991</year>
          <volume>48</volume>
          <fpage>291&#173;296</fpage>
        </element-citation>
      </ref>
      <ref id="ref46">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>M.</surname>
              <given-names>Shoeb</given-names>
            </name>
          </person-group>
          <article-title>Cytotoxic compounds from the Genus Centaurea</article-title>
          <source>Aberdeen, UK: The Robert Gordon University</source>
          <year>2005</year>
        </element-citation>
      </ref>
      <ref id="ref47">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>B.S.</surname>
              <given-names>Siddiqui</given-names>
            </name>
            <name>
              <surname>M.N.</surname>
              <given-names>Kardar</given-names>
            </name>
            <name>
              <surname>S.</surname>
              <given-names>Khan</given-names>
            </name>
          </person-group>
          <article-title>Two New Triterpenoids from Lawsonia inermis</article-title>
          <source>Helvetica Chimica Acta</source>
          <year>2005</year>
          <fpage>2164&#173;2169</fpage>
        </element-citation>
      </ref>
      <ref id="ref48">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>J.C.</surname>
              <given-names>Su</given-names>
            </name>
            <name>
              <surname>K.L.</surname>
              <given-names>Lin</given-names>
            </name>
            <name>
              <surname>C.M.</surname>
              <given-names>Chien</given-names>
            </name>
            <name>
              <surname>C.H.</surname>
              <given-names>Tseng</given-names>
            </name>
            <name>
              <surname>Y.L.</surname>
              <given-names>Chen</given-names>
            </name>
            <name>
              <surname>L.S.</surname>
              <given-names>Chang</given-names>
            </name>
            <name>
              <surname>S.R.</surname>
              <given-names>Lin</given-names>
            </name>
          </person-group>
          <article-title>Furano-1,2-naphthoquinone inhibits EGFR signaling associated with G2/M cell cycle arrest and apoptosis in A549 cells</article-title>
          <source>Cell biochemistry and function</source>
          <year>2010</year>
          <volume>28</volume>
          <fpage>695</fpage>
          <lpage>705</lpage>
        </element-citation>
      </ref>
      <ref id="ref49">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>Y.</surname>
              <given-names>Takeda</given-names>
            </name>
            <name>
              <surname>M.O.</surname>
              <given-names>Fatope</given-names>
            </name>
          </person-group>
          <article-title>New Phenolic Glucosides from Lawsonia inermis</article-title>
          <source>Journal of natural products</source>
          <year>1988</year>
          <volume>51</volume>
          <fpage>725</fpage>
          <lpage>729</lpage>
        </element-citation>
      </ref>
      <ref id="ref50">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>R.D.</surname>
              <given-names>Tripathi</given-names>
            </name>
            <name>
              <surname>H.S.</surname>
              <given-names>Srivastava</given-names>
            </name>
            <name>
              <surname>S.N.</surname>
              <given-names>Dixit</given-names>
            </name>
          </person-group>
          <article-title>A fungitoxic principle from the leaves of lawsonia inermis lam</article-title>
          <source>Experientia</source>
          <year>1978</year>
          <volume>34</volume>
          <fpage>51</fpage>
          <lpage>52</lpage>
        </element-citation>
      </ref>
      <ref id="ref51">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>L.</surname>
              <given-names>Wessjohann</given-names>
            </name>
            <name>
              <surname>M.</surname>
              <given-names>Schmitt</given-names>
            </name>
            <name>
              <surname>J.</surname>
              <given-names>Allwohn</given-names>
            </name>
            <name>
              <surname>G.</surname>
              <given-names>Umbricht</given-names>
            </name>
            <name>
              <surname>J. H.</surname>
              <given-names>Braun</given-names>
            </name>
          </person-group>
          <article-title>Hair dyes and method for dyeing hair with 1, 2, 4- trihydroxynaphthalene glycosides and glucosidases</article-title>
          <source>Ger Offen, 10205500 A10205501 1200308-2</source>
          <year>2003</year>
        </element-citation>
      </ref>
      <ref id="ref52">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>I.</surname>
              <given-names>Yucel</given-names>
            </name>
            <name>
              <surname>G.</surname>
              <given-names>Guzin</given-names>
            </name>
          </person-group>
          <article-title>Topical henna for capecitabine induced hand-foot syndrome</article-title>
          <source>Investigational new drugs</source>
          <year>2008</year>
          <volume>26</volume>
          <fpage>189</fpage>
          <lpage>192</lpage>
        </element-citation>
      </ref>
      <ref id="ref53">
        <element-citation publication-type="journal">
          <person-group person-group-type="author">
            <name>
              <surname>J.</surname>
              <given-names>Zhou</given-names>
            </name>
            <name>
              <surname>L.</surname>
              <given-names>Duan</given-names>
            </name>
            <name>
              <surname>H.</surname>
              <given-names>Chen</given-names>
            </name>
            <name>
              <surname>X.</surname>
              <given-names>Ren</given-names>
            </name>
            <name>
              <surname>Z.</surname>
              <given-names>Zhang</given-names>
            </name>
            <name>
              <surname>F.</surname>
              <given-names>Zhou</given-names>
            </name>
            <name>
              <surname>J.</surname>
              <given-names>Liu</given-names>
            </name>
            <name>
              <surname>D.</surname>
              <given-names>Pei</given-names>
            </name>
            <name>
              <surname>K.</surname>
              <given-names>Ding</given-names>
            </name>
          </person-group>
          <article-title>Atovaquone derivatives as potent cytotoxic and apoptosis inducing agents</article-title>
          <source>Bioorganic &amp; medicinal chemistry letters</source>
          <year>2009</year>
          <volume>19</volume>
          <fpage>5091</fpage>
          <lpage>5094</lpage>
        </element-citation>
      </ref>
    </ref-list>
  </back>
</article>