530
Views
24
CrossRef citations to date
0
Altmetric
Review Article

Biotechnological interventions for harnessing podophyllotoxin from plant and fungal species: current status, challenges, and opportunities for its commercialization

, &
Pages 739-753 | Received 30 Sep 2015, Accepted 20 Apr 2016, Published online: 20 Sep 2016

References

  • Bourgaud F, Gravot A, Milesi S, et al. Production of plant secondary metabolites: a historical perspective. Plant Sci. 2001;161:839–851.
  • Kirakosyan A, Cseke LJ, Kaufman PB. The use of plant cell biotechnology for the production of phytochemicals. In: Kirakosyan A, Kaufman PB, editors. Recent advances in plant biotechnology. Dordrecht: Springer; 2009. p. 15–33.
  • Verpoorte R, Contin A, Memelink J. Biotechnology for the production of plant secondary metabolites. Phytochem Rev. 2002;1:13–25.
  • Iriti M, Faoro F. Chemical diversity and defense metabolism: how plants cope with pathogens and ozone pollution. Int J Mol Sci. 2009;10:3371–3399.
  • Hartmann T. Plant-derived secondary metabolites as defensive chemicals in herbivorous insects: a case study in chemical ecology. Planta 2004;219:1–4.
  • Kamal A, Ali Hussaini SM, Rahim A, et al. Podophyllotoxin derivatives: a patent review (2012–2014). Expert Opin Ther Pat. 2015;25:1025–1034.
  • Chen SW, Wang YH, Jin Y, et al. Synthesis and anti-HIV-1 activities of novel podophyllotoxin derivatives. Bioorg Med Chem Lett. 2007;17:2091–2095.
  • Nagar N, Jat RK, Saharan R, et al. Podophyllotoxin and their glycosidic derivatives. Pharmacophore. 2011;2:124–134.
  • Petrovska BB. Historical review of medicinal plants' usage. Pharmacogn Rev. 2012;6:1–5.
  • Podwyssotzki V. Pharmakologische Studien über Podophyllum peltatum. Arch Exp Pathol Pharmakol. 1880;13:29–52.
  • Hartwell JL, Schrecker AW. Components of podophyllin. V. The constitution of podophyllotoxin. J Am Chem Soc. 1951;73:2909–2916.
  • King LS, Sullivan M. The similarity of the effect of podophyllin and colchicine and their use in the treatment of condylomata acuminata. Science (Washington, DC). 1946;104:244–245.
  • Majumder A, Jha S. Biotechnological approaches for the production of potential anticancer leads podophyllotoxin and paclitaxel: an overview. J Bio Sci. 2009;1:46–69.
  • Castro MA, Miguel del Corral JM, Gordaliza M, et al. Synthesis, cytotoxicity and antiviral activity of podophyllotoxin analogs modified in the E-ring. Eur J Med Chem. 2003;38:899–911.
  • Yu PF, Chen H, Wang J, et al. Design, synthesis and cytotoxicity of novel podophyllotoxin derivatives. Chem Pharm Bull (Tokyo). 2008;56:831–834.
  • Desbène S, Giorgi-Renault S. Drugs that inhibit tubulin polymerization: the particular case of podophyllotoxin and analogs. Curr Med Chem Anticancer Agents. 2002;2:71–90.
  • Ravelli RB, Gigant B, Curmi PA, et al. Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain. Nature. 2004;428: 198–202.
  • Yousefzadi M, Sharifi M, Behmanesh M, et al. Salicylic acid improves podophyllotoxin production in cell cultures of Linum album by increasing the expression of genes related with its biosynthesis. Biotechnol Lett. 2010;32:1739–1743.
  • Gensler WJ, Gatsonis CD. Synthesis of podophyllotoxin. J Am Chem Soc. 1962;84:1748–1749.
  • Andrews RC, Teague SJ, Meyers AI. Asymmetric total synthesis of (−)-podophyllotoxin. J Am Chem Soc. 1988;110:7854–7858.
  • Wu Y, Zhang H, Zhao Y, et al. A new and efficient strategy for the synthesis of podophyllotoxin and its analogs. Org Lett. 2007;9:1199–1102.
  • You Y. Podophyllotoxin derivatives: current synthetic approaches for new anticancer agents. Curr Pharm Des. 2005;11:1695–1717.
  • Ram S. Research practices in herbal medicinal plant: a case study of Podophyllotoxin. Ann Lib Inf Stud. 2010;57:65–71.
  • Nag A, Ahuja PS, Sharma RK. Genetic diversity of high-elevation populations of an endangered medicinal plant. AoB Plants 2014;21:7.
  • Kumari A, Singh HR, Jha A, et al. Transcriptome sequencing of rhizome tissue of Sinopodophyllum hexandrum at two temperatures. BMC Genomics. 2014;15:871.
  • Marques JV, Dalisay DS, Yang H, et al. A multi-omics strategy resolves the elusive nature of alkaloids in Podophyllum species. Mol Biosyst. 2014;10:2838–2849.
  • Lau W, Sattely ES. Six enzymes from mayapple that complete the biosynthetic pathway to the etoposide aglycone. Science. 2015;349:1224–1228.
  • Eyberger AL, Dondapati R, Porter JR. Endophyte fungal isolates from Podophyllum peltatum produce podophyllotoxin. J Nat Prod. 2006;69:1121–1124.
  • Bedir E, Khan I, Moraes RM. Bioprospecting for podophyllotoxin. In: Janick J, Whipkey A, editors. Trends in new crops and new uses. Alexandria, VA: ASHS Press; 2002. p. 54554–54559.
  • Alam MA, Gulati P, Aswini KG, et al. Assessment of genetic diversity among Podophyllum hexandrum genotypes of northwestern Himalayan region for podophyllotoxin production. Indian J Biotechnol. 2009;8:391–399.
  • Renouard S, Lopez T, Hendrawati O, et al. Podophyllotoxin and deoxypodophyllotoxin in Juniperus bermudiana and 12 other Juniperus species: optimization of extraction, method validation, and quantification. J Agric Food Chem. 2011;59:8101–8107.
  • Cushman KE, Maqbool M, Gerard PD, et al. Variation of podophyllotoxin in leaves of Eastern Red Cedar (Juniperus virginiana). Planta Med. 2003;69:477–478.
  • Cushman KE, Moraes RM, Gerard PD, et al. Frequency and timing of leaf removal affect growth and podophyllotoxin content of Podophyllum peltatum in full sun. Planta Med. 2006;72:824–829.
  • Zheljazkov VD, Avula B, Jones AM, et al. Lignan and nutrient concentrations in American mayapple (Podophyllum peltatum L.) in eastern US. Hort Sci. 2009;44:1–5.
  • Ayres DC, Loike JD. Lignans: chemical, biological and clinical properties. Cambridge UK: Cambridge University Press; 1990.
  • Damayanthi Y, Lown JW. Podophyllotoxins: current status and recent developments. Curr Med Chem. 1998;5:205–252.
  • Liu YQ, Yang L, Tian X. Podophyllotoxin: current perspectives. Curr Bioact Compd. 2007;3:37–66.
  • Gordaliza M, García PA, del Corral JM, et al. Podophyllotoxin: distribution, sources, applications and new cytotoxic derivatives. Toxicon 2004;44:441–459.
  • Panda H. Medicinal plants cultivation and their uses. Delhi: Asia Pacific Business Press; 2004.
  • Peng Y, Chen SB, Liu Y, et al. A pharmacophylogenetic study of the Berberidaceae (s.l.). Acta Phytotaxon Sin. 2006;44:241–257.
  • Liu JQ, Chen ZD, Lu AM. Molecular evidence for the sister relationship of the eastern Asia-North American intercontinental species pair in the Podophyllum group (Berberidaceae). Bot Bull Acad Sin. 2002;43:147–154.
  • Porter JR. Podophyllum endophytic fungi. In: Arora R, editor. Medicinal plant biotechnology. Wallingford, Oxfordshire, UK: CABI; 2010. p. 197.
  • Maqbool M. Mayapple: a review of the literature from a horticultural perspective. J Med Plants Res. 2011;5:1037–1045.
  • Chaurasia OP, Ballabh B, Tayade A, et al. Podophyllum L.: an endangered and anticancerous medicinal plant-an overview. Indian J Tradit Knowl. 2012;11:234–241.
  • Pandey H, Nandi SK, Palni LMS. Podophyllotoxin content in leaves and stems of Podophyllum hexandrum Royle from Indian Himalayan region. J Med Plant Res. 2013;7:3237–3241.
  • Paul S, Nandi SK, Palni LMS. Assessment of genetic diversity and interspecific relationships among three species of Podophyllum using AFLP markers and podophyllotoxin content. Plant Syst Evol. 2013;299:1879–1887.
  • Pullaiah T. Encyclopedia of world medicinal plants, vol. 1, published by New Delhi, India: Regency Publication; 2006. p. 1578.
  • Zhao YP, Gong HD, Lu WQ, et al. Growth, photosynthesis and podophyllotoxin accumulation of Dysosma versipellis in response to a light gradient and conservation implications. Chin Sci Bull. 2011;56:2570–2575.
  • Yin ML, Chen ZL. Chemical constituents of Dysosma aurantiocaulis (H.-M.) Hu and Dysosma pleianthum Woods. Zhongguo Zhong Yao Za Zhi. 1989;14:420–421, 447.
  • Zhang J, Shi SY, Peng MJ, et al. Simultaneous determination of five active compounds from Dysosma difformis roots by HPLC. J Liq Chrom Rel Technol. 2014;37:1226–1236.
  • Zhang GH, Quan H, Yuan L, et al. Analysis of podophyllotoxin in different parts of Dysosma tsayuensis Ying by HPLC. Med Plant. 2010;1:54–57.
  • van Uden W, Pras N, Maingré TM. The accumulation of podophyllotoxin-β-D-glucoside by cell suspension cultures derived from the conifer Callitris drummondii. Plant Cell Rep. 1990;9:257–260.
  • Ma C, Yang JS, Luo SR. Study on lignans from Diphylleia sinensis. Yao Xue Xue Bao. 1993;28:690–694.
  • Broomhead AJ, Dewick PM. Tumor-inhibitory aryltetralin lignans in Podophyllum versipelle, Diphylleia cymosa and Diphylleia grayi. Phytochemistry. 1990;29:3831–3838.
  • Udino L, Abaul J, Bourheos P, et al. Lignans from the seeds of Hernandia Sonora. Planta Med. 1999;65:279–281.
  • Konuklugil B. Investigation of podophyllotoxin in some plants in Lamiaceae using HPLC. J Fac Pharm Ankara. 1996;25:23–27.
  • Lautié E, Villarreal ML, Fliniaux MA. Hyptis suaveolens, an alternative source of podophyllotoxin? Planta Med. 2008;74:PC83.
  • Kuhnt M, Rimpler H, Henrich M. Lignans and other compounds from the mixed Indian medicinal plant Hyptis verticillata. Phytochemistry. 1994;36:485–489.
  • Murakana T, Miyata M, Ito K, et al. Production of podophyllotoxin in Juniperus chinensis callus cultures treated with oligosaccharides and a biogenetic precursor. Phytochemistry. 1998;49:491–496.
  • Kusari S, Zühlke S, Spiteller M. Chemometric evaluation of the anti-cancer pro-drug podophyllotoxin and potential therapeutic analogs in Juniperus and Podophyllum species. Phytochem Anal. 2010;22:128–143.
  • Zheljazkov VD, Cantrell CL, Donega MA, et al. Bioprospecting for podophyllotoxin in the Big Horn Mountains, Wyoming. Ind Crops Prod. 2013;43:787–790.
  • Mohagheghzadeh A, Gholami A, Soltani M, et al. Linum mucronatum: organ to organ lignan variations. Z Naturforsch C. 2005;60:508–510.
  • Yang X, Guo S, Zhang L, et al. Selection of producing podophyllotoxin endophytic fungi from podophyllin plant. Nat Prod Res Dev. 2003;15:419–422.
  • Lu L, He J, Yu X, et al. Studies on isolation and identification of endophytic fungi strain SC13 from pharmaceutical plant Sabina vulgaris Ant. and metabolites. Acta Agric Boreali-Occidentalis Sin. 2006;15:85–89.
  • Puri SC, Nazir A, Chawla R, et al. The endophytic fungus Trametes hirsuta as a novel alternative source of podophyllotoxin and related aryl tetralin ligans. J Biotechnol. 2006;122:494–510.
  • Nadeem M, Mauji R, Pravej A, et al. Fusarium solani, P1, a new endophytic podophyllotoxin-producing fungus from roots of Podophyllum hexandrum. Afr J Microbiol Res. 2012;6:2493–2499.
  • Huang JX, Zhang J, Zhang XR, et al. Mucor fragilis as a novel source of the key pharmaceutical agents podophyllotoxin and kaempferol. Pharm Biol. 2014;52:1237–1243.
  • Kour A, Shawl AS, Rehman S, et al. Isolation and identification of an endophytic strain of Fusarium oxysporum producing podophyllotoxin from Juniperus recurva. World J Microb Biot. 2008;24:1115–1121.
  • Zhou X, Zhu H, Liu L, et al. A review: recent advances and future prospects of taxol-producing endophytic fungi. Appl Microbiol Biotechnol. 2010;86:1707–1717.
  • Shweta S, Zuehlke S, Ramesha BT, et al. Endophytic fungal strains of Fusarium solani, from Apodytes dimidiata E. Mey. ex Arn (Icacinaceae) produce camptothecin, 10-hydroxycamptothecin and 9-methoxycamptothecin. Phytochemisry. 2010;71:117–122.
  • Mohana Kumara P, Zuehlke S, Priti V, et al. Fusarium proliferatum, an endophytic fungus from Dysoxylum binectariferum Hook.f, produces rohitukine, a chromane alkaloid possessing anti-cancer activity. Antonie Van Leeuwenhoek. 2012;101:323–329.
  • Kusari S, Lamshöft M, Zühlke S, et al. An endophytic fungus from Hypericum perforatum that produces hypericin. J Nat Prod. 2008;71:159–162.
  • Sachin N, Manjunatha B, Mohana KP, et al. Do endophytic fungi possess pathway genes for plant secondary metabolites? Curr Sci. 2013;104:178–182.
  • Mousa WK, Raizada MN. The diversity of anti-microbial secondary metabolites produced by fungal endophytes: an interdisciplinary perspective. Front Microbiol. 2013;27:65.
  • Zheljazkov VD, Cantrell CL, Astatkie T. Variation in podophyllotoxin concentration in leaves and rhizomes of American mayapple (Podophyllum peltatum L.). Ind Crops Prod. 2011;33:633–637.
  • Nadeem M, Palni LMS, Kumar A, et al. Podophyllotoxin content, above-and below ground biomass in relation to altitude in Podophyllum hexandrum populations from Kumaun region of the Indian central Himalaya. Planta Med. 2007;73:388–391.
  • Sharma T, Singh BM, Sharma NR, et al. Identification of high podophyllotoxin producing biotypes of Podophyllum hexandrum from north-western Himalaya. J Plant Biochem Biotechnol. 2000;9:49–51.
  • Nadeem M, Palni LMS, Purohit AN, et al. Propagation and conservation of Podophyllum hexandrum Royle: an important medicinal herb. Biol Conserv. 2000;92:121–129.
  • Kharkwal AC, Kushwaha R, Prakash O, et al. An efficient method of propagation of Podophyllum hexandrum: an endangered medicinal plant of the Western Himalayas under ex situ conditions. J Nat Med. 2008;62:211–216.
  • Sreenivasulu Y, Chanda SK, Ahuja PS. Endosperm delays seed germination in Podophyllum hexandrum Royle – an important medicinal herb. Seed Sci Technol. 2009;37:10–16.
  • Badhwar BL, Sharma BK. A note on the germination of Podophyllum seeds. Indian Forest. 1963;89:445–447.
  • Kharkwal AC, Prakash OM, Bhattacharya A, et al. Method for inducing improved seed germination in Podophyllum hexandrum Royle. United States; Patent Number 6, 449, 899; 2002.
  • Verma NK, Verma AK, Kumar D. Effect of storage container on seed germination and viability in Aconitum heterophyllum and Podophyllum hexandrum – endangered medicinal plants species of Himalayan region. Biol Forum – Intl J. 2009;1:8–11.
  • Nautiyal MC, Rawat AS, Bhadula SK, et al. Seed germination in Podophyllum hexandrum. Seed Res. 1987;16:206–209.
  • Singh A, Purohit AN, Bhadula SK, et al. Seed production potential and germination behavior in populations of Podophyllum hexandrum Royle. J Plant Biol. 1999;26:51–57.
  • Choudhary DK, Kaul BL, Khan S. Breaking seed dormancy of Podophyllum hexandrum Royle ex. Camb. (syn.P. emodi Wall. Ex. Honigberger). J Non-Timber for Prod. 1996;3:10–12.
  • Li CD, Li W, Li MF, et al. Seed dormancy and germination in endangered plant Podophyllum hexandrum Royle. Bull Bot Res. 2008;28:618–621.
  • Simonnet X, Quennoz M, Sigg S, et al. Seed germination behavior of the endangered medicinal plant Podophyllum hexandrum. Acta Hortic (ISHS). 2012;955:309–313.
  • Sharma RK, Sharma S, Sharma SS. Storage dependent changes in dormancy and germination of Himalayan Mayapple (Podophyllum hexandrum Royle) seeds and their response to Gibberellic acid. J Herbs Spices Med Plants. 2010;16:69–82.
  • Sharma R, Sharma S, Sharma SS. Seed germination behavior of some medicinal plants of Lahaul and Spiti cold desert (Himachal Pradesh): implications for conservation and cultivation. Curr Sci. 2006;90:1113–1118.
  • Li W, Li M, Yang DL, et al. Production of podophyllotaxin by root culture of Podophyllum hexandrum Royle. Electron J Biol. 2009;5:34–39.
  • Rust RW, Roth RR. Seed production and seedling establishment in the mayapple, Podophyllum peltatum L. Am Midland Natural. 1981;105:51–60.
  • Nivot N, Olivier A, Lapointe L. Vegetative propagation of five northern forest understory plant species from either rhizome or stem sections. Hort Sci. 2008;43:1531–1537.
  • Pandey H, Nandi S, Chandra B, et al. Ga3 induced flowering in Podophyllum hexandrum Royle: a rare alpine medicinal herb. Acta Physiol Plant. 2001;23:467–474.
  • Moraes MR, Lata H, Bedir E, et al. The American mayapple and its potential for podophyllotoxin production. Trends in new crops and new uses. Alexandria (VA): ASHS Press; 2002. p. 527–532.
  • Maqbool M, Cushman KE, Moraes RM. Propagule type and planting time for field established Mayapple. Trends in new crops and new uses. In: Janick J, Whipkey A, editors. Alexandria (VA): ASHS Press; 2002. p. 533–536.
  • Maqbool M, Cushman KE, Moraes RM, et al. Overcoming dormancy of mayapple rhizome segments with low temperature exposure. Hort Sci. 2004;39:307–311.
  • Kadkade PG. Formation of podophyllotoxins by Podophyllum peltatum tissue cultures. Naturwissenschaften. 1981;68:481–482.
  • Uden WV, Pras N, Visser JF, et al. Detection and identification of podophyllotoxin produced by cell cultures derived from Podophyllum hexandrum Royle. Plant Cell Rep. 1989;8:165–168.
  • Arumugam N, Bhojwani SS. Somatic embryogenesis in tissue cultures of Podophyllum hexandrum. Can J Bot. 1990;68:487–491.
  • Bisht SS, Bisht S. Callus induction studies in different explants of Podophyllum hexandrum (Royle). Acta Adv Agric Sci. 2014;9–14.
  • Chakraborty A, Bhattacharya D, Ghanta S, et al. An efficient protocol for in vitro regeneration of Podophyllum hexandrum, a critically endangered medicinal plant. Indian J Biotechnol. 2010;9:217–220.
  • Guo Q, Zhou J, Wang Z, et al. In vitro rooting of Podophyllum hexandrum and transplanting technique. Engineering. 2012;4:142–145.
  • Sadowska A, Wiweger M, Lata B, et al. In vitro propagation of Podophyllum peltatum L. by the cultures of embrya and divided embrya. Biol Plant. 1997;39:331–336.
  • Kim YS, Lim S, Choi YE, et al. High frequency plant regeneration via somatic embryogenesis in Podophyllum peltatum L., an important source of anticancer drug. Curr Sci. 2007;92:662–666.
  • Sultan P, Shawl AS, Ramteke PW, et al. In vitro propagation for mass multiplication of Podophyllum hexandrum: a high value medicinal herb. Asian J Plant Sci. 2006;5:179–184.
  • Anrini M, Jha S. Characterization of podophyllotoxin yielding cell lines of Podophyllum hexandrum. Caryologia. 2009;62:220–235.
  • Fujii Y. Podophyllum spp. In vitro regeneration and production of podophyllotoxins. In: Bajaj YPS, editor. Biotechnology in agriculture and forestry, medicinal and aromatic plants. Heidelberg: Springer; 1991. p. 362–375.
  • Velóz RA, Cardoso-Taketa A, Villarreal ML. Production of podophyllotoxin from roots and plantlets of Hyptis suaveolens cultivated in vitro. Pharmacognosy Res. 2013;5:93–102.
  • Premjet D, Tachibana S. Production of podophyllotoxin by immobilized cell cultures of Juniperus chinensis. Pak J Biol Sci. 2004;7:1130–1134.
  • Bamfarahnak H, Gholami A, Bakzadeh Z, et al. Evaluation of thermal-stress on the accumulation of podophyllotoxin in shoot in vitro cultures of Linum persicum. Res J Pharmacogn. 2014;1:3–9.
  • Shams-Ardakani M, Hemmati S, Mohagheghzadeh A. Effect of elicitation on the enhancement of podophyllotoxin biosynthesis in suspension cultures of Linum album. J Pharm Sci. 2005;13:56–60.
  • Smollny T, Wichers H, Kalenberg S, et al. Accumulation of podophyllotoxin and related lignans in cell suspension cultures of Linum album. Phytochemistry. 1998;48:975–979.
  • Samadi A, Jafari M, Nejhad NM, et al. Podophyllotoxin and 6-methoxy podophyllotoxin production in hairy root cultures of Liunm mucronatum ssp. mucronatum. Pharmacogn Mag. 2014;10:154–160.
  • Moraes-Cerdeira RM, Burandt CL Jr, Bastos JK, et al. In vitro propagation of Podophyllum peltatum. Planta Med. 1998;64:42–46.
  • Anbazhagan V, Ahn C, Harada E, et al. Podophyllotoxin production via cell and adventitious root cultures of Podophyllum peltatum. In Vitro Cell Dev Pl. 2008;44:494–501.
  • Chattopadhyay S, Srivastava AK, Bhojwani SS, et al. Development of suspension culture of Podophyllum hexandrum for the production of podophyllotoxin. Biotechnol Lett. 2001;23:2063–2066.
  • Heyenga AG, Lucas JA, Dewick PM. Production of tumour-inhibitory lignans by callus cultures of Podophyllum hexandrum. Plant Cell Rep. 1990;9:382–385.
  • Woerdenbag HJ, Pras N, Van Uden W, et al. Increased podophyllotoxin production in Podophyllum hexandrum cell suspension cultures after feeding coniferyl alcohol as a b-cyclodextrin complex. Plant Cell Rep. 1990;9:97–100.
  • Chattopadhyay S, Srivastava AK, Bhojwani SS, et al. Production of podophyllotoxin by plant cell cultures of Podophyllum hexandrum in bioreactor. J Biosci Bioeng. 2002;93:215–220.
  • Chattopadhyay S, Bisaria VS, Bhojwani SS, et al. Enhanced production of podophyllotoxin by fed-batch cultivation of Podophyllum hexandrum. Can J Chem Eng. 2003;81:1011–1018.
  • Ahmad R, Sharma VK, Rai AK. Production of lignans in callus culture of Podophyllum hexandrum. Trop J Pharm Res. 2007;6:803–808.
  • Hussain MS, Fareed S, Ansari S, et al. Current approaches toward production of secondary plant metabolites. J Pharm Bioallied Sci. 2012;4:10–20.
  • Chattopadhyay S, Mehra RS, Srivastava AK, et al. Effect of major nutrients on podophyllotoxin production in Podophyllum hexandrum suspension cultures. Appl Microbiol Biotechnol. 2003;60:541–546.
  • Majumder A, Jha S. Growth and podophyllotoxin production in callus and cell suspension cultures of Podophyllum hexandrum. Proceeding of National Symposium on Plant Biotechnology: New Frontiers, CIMAP, Lucknow; 2007, p. 433-8.
  • Ramachandra RS, Ravishankar GA. Plant cell cultures: chemical factories of secondary metabolites. Biotechnol Adv. 2002;20:101–153.
  • Uden WV, Pras N, Malingre TM. On the improvement of the podophyllotoxin production by phenylpropanoid precursor feeding to cell cultures of Podophyllum hexandrum Royle. Plant Cell Tissue Organ Cult. 1990;23:217–224.
  • Bhattacharyya D, Sinha R, Ghanta S, et al. Proteins differentially expressed in elicited cell suspension culture of Podophyllum hexandrum with enhanced podophyllotoxin content. Proteome Sci. 2012;10:34.
  • van Fürden B, Humburg A, Fuss E. Influence of methyl jasmonate on podophyllotoxin and 6-methoxypodophyllotoxin accumulation in Linum album cell suspension cultures. Plant Cell Rep. 2005;24:312–317.
  • Schmitt J, Petersen M. Influence of methyl jasmonate and coniferyl alcohol on pinoresinol and matairesinol accumulation in a Forsythia × intermedia suspension culture. Plant Cell Rep. 2002;20:885–890.
  • Bahabadi SE, Sharifi M, Chashmi NA, et al. Significant enhancement of lignans accumulation in hairy root cultures of Linum album using biotic elicitors. Acta Physiol Plant. 2014;36:3325–3331.
  • Bahabadi SE, Sharifi M, Safaie N, et al. Increased lignan biosynthesis in the suspension cultures of Linum album by fungal extracts. Plant Biotechnol Rep. 2011;5:367–373.
  • Tahsili J, Sharifi M, Safaie N, et al. Induction of lignans and phenolic compounds in cell culture of Linum album by culture filtrate of Fusarium graminearum. J Plant Interact. 2014;9:412–417.
  • Giri A, Giri CC, Dhingra V, et al. Enhanced podophyllotoxin production from Agrobacterium rhizogenes transformed cultures of Podophyllum hexandrum. Nat Prod Lett. 2001;15:229–235.
  • Chashmi NA, Sharifi M, Yousefzadi M, et al. Analysis of 6-methoxy podophyllotoxin and podophyllotoxin in hairy root cultures of Linum album Kotschy ex Boiss. Med Chem Res. 2012;22:745–752.
  • Farkya S, Rajouria G, Kumar V, et al. High podophyllotoxin producing hairy root line of Linum Album: influence of carbohydrates, temperature and photoperiod. Curr Biotechnol. 2013;2:134–141.
  • Lin H, Kian HK, Doran PM. Production of podophyllotoxin using cross-species coculture of Linum flavum hairy roots and Podophyllum hexandrum cell suspensions. Biotechnol Prog. 2003;19:1417–1426.
  • Georgiev MI, Weber J, Maciuk A. Bioprocessing of plant cell cultures for mass production of targeted compounds. Appl Microbiol Biotechnol. 2009;83:809–823.
  • Chopra RN, Chopra IC, Handa KL, et al. Chopra’s indigenous drugs of India. Reprint 2nd ed. Calcutta: Academic Publisher; 1958.
  • Meijer W. Podophyllum peltatum: mayapple a potential new cash crop plant of Eastern North America. Econ Bot. 1974;28:68–72.
  • Prasad P. Impact of cultivation on active constituents of the medicinal plants Podophyllum hexandrum and Aconitum heterophyllum in Sikkim. Plant Genet Resour Newslett. 2000;124:33–35.
  • Verpoorte R, Der Heijden RV, Hoopen HJG, et al. Metabolic engineering of plant secondary metabolite pathways for the production of fine chemicals. Biotechnol Lett. 1999;21:467–479.
  • Pickens LB, Tang Y, Chooi YH. Metabolic engineering for the production of natural products. Annu Rev Chem Biomol Eng. 2011;2:211–236.
  • Schmidt J, Petersen M. Pinoresinol and matairesinol accumulation in a Forsythia x intermedia cell suspension culture. Plant Cell Tiss Org Cult. 2002;68:91–98.
  • Kim HJ, Ono E, Morimoto K, et al. Metabolic engineering of lignan biosynthesis in Forsythia cell culture. Plant Cell Physiol. 2009;50:2200–2209.
  • Hano C, Martin I, Fliniaux O, et al. Pinoresinol-lariciresinol reductase gene expression and secoisolariciresinol diglucoside accumulation in developing flax (Linum usitatissimum) seeds. Planta. 2006;224:1291–1301.
  • Arroo R, Alfermann AW, Medarde M, et al. Plant cell factories as a source for anti-cancer lignans. Phytochem Rev. 2002;1:27–35.
  • Zare K, Movafeghi A, Mohammadi SA, et al. New phenolics from Linum mucronatum subsp. orientale. Bioimpacts. 2014;4:117–122.
  • Seidel V, Windhövel J, Eaton G, et al. Biosynthesis of podophyllotoxin in Linum album cell cultures. Planta. 2002;215:1031–1039.
  • Esmaeilzadeh Bahabadi S, Sharifi M, Behmanesh M, et al. Time-course changes in fungal elicitor-induced lignan synthesis and expression of the relevant genes in cell cultures of Linum album. J Plant Physiol. 2012;169:487–491.
  • Chashmi NA, Sharifi M, Behmanesh M. Lignan enhancement in hairy root cultures of Linum album using coniferaldehyde and methylenedioxy cinnamic acid. Prep Biochem Biotechnol. 2015;46:454–460.
  • Sasheva P, Ionkova I, Stoilova N. Methyl jasmonate induces enhanced podophyllotoxin production in cell cultures of Thracian flax (Linum thracicum ssp. thracicum). Nat Prod Commun. 2015;10:1225–1228.
  • Sedaghat S, Ezatzadeh E, Alfermann AW. Podophyllotoxin from suspension culture of Linum album. Nat Prod Res. 2008;22:984–989.
  • Ionkova I, Antonova I, Momekov G, et al. Production of podophyllotoxin in Linum linearifolium in vitro cultures. Pharmacogn Mag. 2010;6:180–185.
  • Cong LH, Dauwe R, Lequart M, et al. Kinetics of glucosylated and non-glucosylated aryltetralin lignans in Linum hairy root cultures. Phytochemistry. 2015;115:70–78.
  • Bhattacharyya D, Chattopadhyay S. Characterization of podophyllotoxin biosynthetic pathway and future prospect of podophyllotoxin production from Podophyllum hexandrum Royle. Chem Biol Lett. 2015;2:12–21.
  • Marques JV, Kim KW, Lee C, et al. Next generation sequencing in predicting gene function in podophyllotoxin biosynthesis. J Biol Chem. 2013;288:466–479.
  • Kumar P, Pal T, Sharma N, et al. Expression analysis of biosynthetic pathway genes vis-à-vis podophyllotoxin content in Podophyllum hexandrum Royle. Protoplasma. 2015;252:1253–1262.
  • O'Connor. Fighting cancer while saving the mayapple. Science. 2015;349:1167–1168.
  • Satake H, Ono E, Murata J. Recent advances in the metabolic engineering of lignan biosynthesis pathways for the production of transgenic plant-based foods and supplements. J Agric Food Chem. 2013;61:11721–11729.
  • Yonekura-Sakakibara K, Saito K. Functional genomics for plant natural product biosynthesis. Nat Prod Rep. 2009;26:1466–1487.
  • Mao Y, Zhang Y, Xu C, et al. Comparative transcriptome resources of two Dysosma species (Berberidaceae) and molecular evolution of the CYP719A gene in Podophylloideae. Mol Ecol Resour. 2015;16:228–241.
  • Guo R, Mao YR, Cai JR, et al. Characterization and cross-species transferability of EST–SSR markers developed from the transcriptome of Dysosma versipellis (Berberidaceae) and their application to population genetic studies. Mol Breeding. 2014;34:11–14.
  • Bhattacharyya D, Sinha R, Hazra S, et al. De novo transcriptome analysis using 454 pyrosequencing of the Himalayan Mayapple, Podophyllum hexandrum. BMC Genomics. 2013;14:748.
  • Yousefzadi M, Sharifi M, Behmanesh M, et al. The effect of light on gene expression and podophyllotoxin biosynthesis in Linum album cell culture. Plant Physiol Biochem. 2012;56:41–46.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.