Phytochemistry Reviews

, Volume 13, Issue 4, pp 893–913 | Cite as

Biotechnological approaches for producing aryltetralin lignans from Linum species

  • S. Malik
  • O. Bíba
  • J. Grúz
  • R. R. J. Arroo
  • M. Strnad
Article

Abstract

The genus Linum includes more than 230 globally distributed species, which have attracted great interest as they grow rapidly and are already sources of commercially important products, e.g. flax and linseed oil. Furthermore, they contain lignans such as podophyllotoxin (PTOX), deoxypodophyllotoxin (a precursor of both PTOX and 6-methoxypodophyllotoxin, the latter via β-peltatin, and β-peltatin-A-methyl ether) and various derivatives. Lignans are natural compounds derived from two 8,8′-linked C6C3 (propylbenzene) units. PTOX is an aryltetralin-lignan with strong cytotoxic and antiviral activities. Thus, it is used as a starting material for producing various semisynthetic derivatives that are widely used in chemotherapy, such as etoposide, teniposide and etopophos. It is currently produced largely from Podophyllum hexandrum and P. peltatum, slow-growing endangered species of the Berberidaceae. Hence, the possibility of producing it from Linum, especially members of section Syllinum under either in vitro or ex vitro conditions is highly attractive. This review summarizes related research, focusing on in vitro production of aryltetralin lignans from various Linum species and possible biotechnological strategies to improve their production. The key pathways, enzymes and genes involved are highlighted and future challenges that must be met to allow viable, large-scale production of this anticancer drug lead are discussed.

Keywords

6-Methoxypodophyllotoxin Anticancer drugs In vitro cultures Lignans Podophyllotoxin Medicinal plants 

Abbreviations

dPTOX

Deoxypodophyllotoxin

DW

Dry weight

6-MPTOX

6-Methoxypodophyllotoxin

PTOX

Podophyllotoxin

5′-d-6-MPTOX

5′-Demethoxy-6-methoxypodophyllotoxin

MeJ

Methyl jasmonate

SA

Salicylic acid

References

  1. Arroo RRJ, Alfermann AW, Medarde M, Petersen M, Pras N, Woolley JG (2002) Plant cell factories as a source for anti-cancer lignans. Phytochem Rev 1(1):27–35Google Scholar
  2. Attoumbré J, Charlet S, Baltora-Rosset S, Hano C, Raynaud-Le Grandic S, Gillet F, Bensaddek L, Mesnard F, Fliniaux MA (2006) High accumulation of dehydrodiconiferyl alcohol-4-β-d-glucoside in free and immobilized Linum usitatissimum cell cultures. Plant Cell Rep 25(8):859–864PubMedGoogle Scholar
  3. Bahabadi SE, Sharifi M, Safaie N, Murata J, Yamagaki T, Satake H (2011) Increased lignan biosynthesis in the suspension cultures of Linum album by fungal extracts. Plant Biotechnol Rep 5(4):367–373Google Scholar
  4. Bahabadi SE, Sharifi M, Behmanesh M, Safaie N, Murata J, Araki R, Yamagaki T, Satake H (2012) Time-course changes in fungal elicitor-induced lignan synthesis and expression of the relevant genes in cell cultures of Linum album. J Plant Physiol 169(5):487–491Google Scholar
  5. Baldi A, Jain A, Gupta N, Srivastava AK, Bisaria VS (2008a) Co-culture of arbuscular mycorrhiza-like fungi (Piriformospora indica and Sebacina vermifera) with plant cells of Linum album for enhanced production of podophyllotoxins: a first report. Biotechnol Lett 30(9):1671–1677PubMedGoogle Scholar
  6. Baldi A, Srivastava AK, Bisaria VS (2008b) Effect of aeration on production of anticancer lignans by cell suspension cultures of Linum album. Appl Biochem Biotechnol 151(2–3):547–555PubMedGoogle Scholar
  7. Baldi A, Srivastava AK, Bisaria VS (2008c) Improved podophyllotoxin production by transformed cultures of Linum album. Biotechnol J 3(9–10):1256–1263PubMedGoogle Scholar
  8. Baldi A, Farkya S, Jain A, Gupta N, Mehra R, Datta V, Srivastava AK, Bisaria VS (2010) Enhanced production of podophyllotoxins by co-culture of transformed Linum album cells with plant growth-promoting fungi. Pure Appl Chem 82(1):227–241Google Scholar
  9. Berim A, Spring O, Conrad J, Maitrejean M, Boland W, Petersen M (2005) Enhancement of lignan biosynthesis in suspension cultures of Linum nodiflorum by coronalon, indanoyl-isoleucine and methyl jasmonate. Planta 222(5):769–776PubMedGoogle Scholar
  10. Berlin J, Wray V, Mollenschott C, Sasse F (1986) Formation of β-peltatin-A methyl ether and coniferin by root cultures of Linum flavum. J Nat Prod 49(3):435–439PubMedGoogle Scholar
  11. Berlin J, Bedorf N, Mollenschott C, Wray V, Sasse F, Höfle G (1988) On the podophyllotoxins of root cultures of Linum flavum. Planta Med 54(3):204–206PubMedGoogle Scholar
  12. Bhojwani SS, Rajdan MK (1996) Tissue culture media. In: Bhojwani SS, Rajdan MK (eds) Plant tissue culture, theory and practice. Elsevier, New YorkGoogle Scholar
  13. Broomhead AJ, Rahman MMA, Dewick PM, Jackson DE, Lucas JA (1991) Matairesinol as precursor of Podophyllum lignans. Phytochemistry 30(5):1489–1492Google Scholar
  14. Burbulis N, Blinstrubiene A, Venskutoniene E, Katauskyte L (2005) Organogenesis in callus cultures of Linum usitatissimum L. Acta Univ Latviensis 691:129–135Google Scholar
  15. Chashmi NA, Sharifi M, Yousefzadi M, Behmanesh M, Palazon J (2011) The production of cytotoxic lignans by hairy root cultures of Linum album. World Acad Sci Eng Technol 80:401–402Google Scholar
  16. Chashmi NA, Sharifi M, Yousefzadi M, Behmanesh M, Rezadoost H, Cardillo A, Palazon J (2013) Analysis of 6-methoxy podophyllotoxin and podophyllotoxin in hairy root cultures of Linum album Kotschy ex Boiss. Med Chem Res 22(2):745–752Google Scholar
  17. Chu A, Dinkova A, Davin LB, Bedgar DL, Lewis NG (1993) Stereospecificity of (+)-pinoresinol and (+)-lariciresinol reductases from Forsythia intermedia. J Biol Chem 268(36):27026–27033PubMedGoogle Scholar
  18. Davin LB, Lewis NG (2000) Dirigent proteins and dirigent sites explain the mystery of specificity of radical precursor coupling in lignan and lignin biosynthesis. Plant Physiol 123(2):453–461PubMedCentralPubMedGoogle Scholar
  19. Dharmawardhana DP, Ellis BE, Carlson JE (1995) A β-glucosidase from lodgepole pine xylem specific for the lignin precursor coniferin. Plant Physiol 107(2):331–339PubMedCentralPubMedGoogle Scholar
  20. Empt U, Alfermann AW, Pras N, Petersen M (2000) The use of plant cell cultures for the production of podophyllotoxin and related lignans. J Appl Bot 74(3–4):145–150Google Scholar
  21. Farkya S, Bisaria VS (2008) Exogenous hormones affecting morphology and biosynthetic potential of hairy root line (LYR2i) of Linum album. J Biosci Bioeng 105(2):140–146PubMedGoogle Scholar
  22. Fay MF (1992) Conservation of rare and endangered plants using in vitro methods. In Vitro Cell Dev Biol Plant 28:1–4Google Scholar
  23. Fay DA, Ziegler HW (1985) Botanical sources differentiation of Podophyllum resin by high performance liquid chromatography. J Liqid Chromatogr 8(8):1501–1506Google Scholar
  24. Federolf K, Alfermann AW, Fuss E (2007) Aryltetralin-lignan formation in two different cell suspension cultures of Linum album: deoxypodophyllotoxin 6-hydroxylase, a key enzyme for the formation of 6-methoxypodophyllotoxin. Phytochemistry 68(10):1397–1406PubMedGoogle Scholar
  25. Ford JD, Huang KS, Wang HB, Davin LB, Lewis NG (2001) Biosynthetic pathway to the cancer chemopreventive secoisolariciresinol diglucoside—hydroxymethyl glutaryl ester-linked lignan oligomers in flax (Linum usitatissimum) seed. J Nat Prod 64(11):1388–1397PubMedGoogle Scholar
  26. Fuss E (2003) Lignans in plant cell and organ cultures: an overview. Phytochem Rev 2:307–320Google Scholar
  27. Gamborg OL, Miller RA, Ojima K (1968) Nutrient requirement of suspension culture of soybean root cells. Exp Cell Res 50:151–158Google Scholar
  28. Gordaliza M, García PA, del Corral JM, Castro MA, Gómez-Zurita MA (2004) Podophyllotoxin: distribution, sources, applications and new cytotoxic derivatives. Toxicon 44(4):441–459PubMedGoogle Scholar
  29. Hande KR (2008) Topoisomerase II inhibitors. Update Cancer Ther 3(1):13–26Google Scholar
  30. Hano C, Addi M, Bensaddek L, Crônier D, Baltora-Rosset S, Doussot J, Maury S, Mesnard F, Chabbert B, Hawkins S, Lainé E, Lamblin F (2006a) Differential accumulation of monolignol-derived compounds in elicited flax (Linum usitatissimum) cell suspension cultures. Planta 223(5):975–989PubMedGoogle Scholar
  31. Hano C, Martin I, Fliniaux O, Legrand B, Gutierrez L, Arroo RRJ, Mesnard F, Lamblin F, Lainé E (2006b) Pinoresinol–lariciresinol reductase gene expression and secoisolariciresinol diglucoside accumulation in developing flax (Linum usitatissimum) seeds. Planta 224(6):1291–1301PubMedGoogle Scholar
  32. Hemmati S, Schmidt TJ, Fuss E (2007) (+)-Pinoresinol/(−)-lariciresinol reductase from Linum perenne Himmelszelt involved in the biosynthesis of justicidin B. FEBS Lett 581(4):603–610PubMedGoogle Scholar
  33. Ionkov T, Ionkova I, Sasheva P (2012) Strategy to control the production of rare anticancer substances in the endangered plant Linum linearifolium in bioreactor. Indian J Fundam Appl Life Sci 2(1):170–176Google Scholar
  34. Ionkova I (2008) Anticancer compounds from in vitro cultures of rare medicinal plants. Phcog Rev 2(4):206–218Google Scholar
  35. Ionkova I (2009) Effect of methyl jasmonate on production of ariltetralin lignans in hairy root cultures of Linum tauricum. Pharmacognosy Res 1(3):102–105Google Scholar
  36. Ionkova I, Fuss E (2009) Influence of different strains of Agrobacterium rhizogenes on induction of hairy roots and lignan production in Linum tauricum ssp. Tauricum. Pharmacogn Mag 4(17):14–18Google Scholar
  37. Ionkova I, Antonova I, Momekov G, Fuss E (2010) Production of podophyllotoxin in Linum linearifolium in vitro cultures. Pharmacogn Mag 6(23):180–185PubMedCentralPubMedGoogle Scholar
  38. Jackson DE, Dewick PM (1984a) Biosynthesis of Podophyllum lignans—I. Cinnamic acid precursors of podophyllotoxin in Podophyllum hexandrum. Phytochemistry 23(5):1029–1035Google Scholar
  39. Jackson DE, Dewick PM (1984b) Biosynthesis of Podophyllum lignans—II. Interconversions of aryltetralin lignans in Podophyllum hexandrum. Phytochemistry 23(5):1037–1042Google Scholar
  40. Javidnia K, Miri R, Rezai H, Jafari A, Azarmehr A, Amirghofran Z (2005) Biological activity and aryltetraline lignans of Linum persicum. Pharm Biol 43(6):547–550Google Scholar
  41. Kamil WM, Dewick PM (1986a) Biosynthesis of the lignans α- and β-peltatin. Phytochemistry 25(9):2089–2092Google Scholar
  42. Kamil WM, Dewick PM (1986b) Biosynthetic relationship of aryltetralin lactone lignans to dibenzylbutyrolactone lignans. Phytochemistry 25(9):2093–2102Google Scholar
  43. Kanmaz EO, Ova G (2013) The effective parameters for subcritical water extraction of SDG lignan from flaxseed (Linum usitatissimum L.) using accelerated solvent extractor. Eur Food Res Technol 237:159–166Google Scholar
  44. Kartal M, Konuklugil B, Indrayanto G, Alfermann AW (2004) Comparison of different extraction methods for the determination of podophyllotoxin and 6-methoxypodophyllotoxin in Linum species. J Pharmaceut Biomed 35(3):441–447Google Scholar
  45. Konuklugil B (1998) Arytetralin lignans from Linum catharticum L. Biochem Syst Ecol 26(7):795–796Google Scholar
  46. Konuklugil B (2005) Aryltetralin lignans from Linum cariense. Chem Nat Compd 41(3):306–307Google Scholar
  47. Konuklugil B, Schmidt TJ, Alfermann AW (1999) Accumulation of aryltetralin lactone lignans in cell suspension cultures of Linum nodiflorum L. Planta Med 65:587–588PubMedGoogle Scholar
  48. Konuklugil B, Schmidt TJ, Alfermann AW (2001) Accumulation of lignans in suspension cultures of Linum mucronatum ssp. armenum (Bordz.) Davis. Z Naturforsch C 56(11–12):1164–1165PubMedGoogle Scholar
  49. Konuklugil B, Ionkova I, Vasilev T, Schmidt TJ, Windhovec J, Fuss E, Alfermann AW (2007) Lignans from Linum species of sections Syllinum and Linum. Nat Prod Res 21(1):1–6PubMedGoogle Scholar
  50. Kranz K, Petersen M (2003) β-Peltatin 6-O-methyltransferase from suspension cultures of Linum nodiflorum. Phytochemistry 64(2):453–458PubMedGoogle Scholar
  51. Kuhlmann S, Kranz K, Lücking B, Alfermann AW, Petersen M (2002) Aspects of cytotoxic lignan biosynthesis in suspension cultures of Linum nodiflorum. Phytochem Rev 1(1):37–43Google Scholar
  52. Kumar R, Sharma N, Malik S, Bhushan S, Sharma UK, Kumari D, Sinha AK, Sharma M, Ahuja PS (2011) Cell suspension culture of Arnebia euchroma (Royle) Johnston – A potential source of naphthoquinone pigments J Med Plants Res 5(25):6048–6054Google Scholar
  53. Lee KH, Xiao Z (2003) Lignans in treatment of cancer and other diseases. Phytochem Rev 2(3):341–362Google Scholar
  54. Lin HW, Kwok KH, Doran PM (2003) Development of Linum flavum hairy root cultures for production of coniferin. Biotech Lett 25(7):521–525Google Scholar
  55. Linsmaier EM, Skoog F (1965) Organic growth factor requirements of tobacco tissue cultures. Physiol Plantarum 18(1):100–127Google Scholar
  56. Lücking B (2001) Charakterisierung von Suspensionskulturen von Linum nodiflorum L. Diploma Thesis, Universities of Marburg and Halle-WittenbergGoogle Scholar
  57. Malik S, Kumar R, Vats SK, Bhushan S, Sharma M, Ahuja  PS (2009) Regeneration in Rheum emodi Wall.: a step towards conservation of an endangered medicinal plant species. Eng Life Sci 2:130–134Google Scholar
  58. Malik S, Sharma S, Sharma M, Ahuja  PS (2010) Direct shoot regeneration from intact leaves of Arnebia euchroma (Royle) Johnston using thidiazuron. Cell Biol Int 34(5):537–542Google Scholar
  59. Malik S, Cusidó RM, Mirjalili MH, Moyano E, Palazón J, Bonfill M (2011) Production of the anticancer drug taxol in Taxus baccata suspension cultures: a review. Process Biochem 46(1):23–34Google Scholar
  60. Malik S, Mirjalili MH, Fett-Neto AG, Mazzafera P, Bonfill M (2013) Living between two worlds: two-phase culture systems for producing plant secondary metabolites. Crit Rev Biotechnol 33(1):1–22PubMedGoogle Scholar
  61. McDill J, Repplinger M, Simpson BB, Kadereit WJ (2009) The phylogeny of Linum and Linaceae subfamily Linoideae, with implications for their systematics, biogeography, and evolution of heterostyly. Syst Bot 34(2):386–405Google Scholar
  62. Mikame K, Sakakibara N, Umezawa T, Shimada M (2002) Lignans of Linum flavum var. compactum. J Wood Sci 48(5):440–445Google Scholar
  63. Mohagheghzadeh A, Schmidt TJ, Alfermann AW (2002) Arylnaphthalene lignans from in vitro cultures of Linum austriacum. J Nat Prod 65(1):69–71PubMedGoogle Scholar
  64. Mohagheghzadeh A, Hemmati S, Mehregan I, Alfermann AW (2003) Linum persicum: lignans and placement in Linaceae. Phytochem Rev 2(3):363–369Google Scholar
  65. Mohagheghzadeh A, Gholamia A, Soltania M, Hemmati S, Alfermann AW (2005) Linum mucronatum: organ to organ lignan variations. Z Naturforsch 60c(5-6):508–510Google Scholar
  66. Mohagheghzadeh A, Hemmati S, Alfermann AW (2006) Quantification of aryltetralin lignans in Linum album organs and in vitro cultures. Iran J Pharm Sci 2(1):47–56Google Scholar
  67. Mohagheghzadeh A, Gholamia A, Hemmati S, Ardakanic MRS, Schmidt TJ, Alfermann AW (2007) Root cultures of Linum species section Syllinum as rich sources of 6-methoxypodophyllotoxin. Z Naturforsch 62c(1–2):43–49Google Scholar
  68. Mohagheghzadeh A, Gholamia A, Hemmati S, Dehshahr S (2008) Bag culture: a method for root–root co-culture. Z Naturforsch 63c(1):157–160Google Scholar
  69. Mohammed MMD, Chen M, Zhai L, Ibrahim NA (2010) The cytotoxic activity of Linum grandiflorum leaves. Eur J Chem 1(2):110–114Google Scholar
  70. Molog GA, Empt U, Kuhlmann S, van Uden W, Pras N, Alfermann AW, Petersen M (2001) Deoxypodophyllotoxin 6-hydroxylase, a cytochrome P450 monooxygenase from cell cultures of Linum flavum involved in lignan biosynthesis. Planta 214(2):288–294PubMedGoogle Scholar
  71. Moss GP (2000) Nomenclature of lignans and neolignans (IUPAC recommendations 2000). Pure Appl Chem 72(8):1493–1523Google Scholar
  72. Murashige T, Skoog F (1962) A revised medium for rapid growth and bioassays with tobacco tissue cultures. Physiol Plant 15:473–497Google Scholar
  73. Nakatsubo T, Mizutani M, Suzuki S, Hattori T, Umezawa T (2008) Characterization of Arabidopsis thaliana pinoresinol reductase, a new type of enzyme involved in lignan biosynthesis. J Biol Chem 283(23):15550–15557PubMedCentralPubMedGoogle Scholar
  74. Okunishi T, Umezawa T, Shimada M (2000) Enantiomeric compositions and biosynthesis of Wikstroemia sikokiana lignans. J Wood Sci 46(3):234–242Google Scholar
  75. Oostdam A, Mol JNM, van der Plas LHW (1993) Establishment of hairy root cultures of Linum flavum producing the lignan 5-methoxypodophyllootoxin. Plant Cell Rep 12(7–8):474–477PubMedGoogle Scholar
  76. Rahman MMA, Dewick PM, Jackson DE, Lucas JA (1990) Biosynthesis of lignans in Forsythia intermedia. Phytochemistry 29(6):1841–1846Google Scholar
  77. Rao RS, Ravishankar GA (2002) Plant cell cultures: chemical factories of secondary metabolites. Biotechnol Adv 20(2):101–153PubMedGoogle Scholar
  78. Rogers CM (1982) The systematics of Linum sect. Linopsis (Linaceae). Plant Syst Evol 140(2-3):225–334Google Scholar
  79. Rout GR, Samantaray S, Das P (2000) In vitro manipulation and propagation of medicinal plants. Biotechnol Adv 18(2):91–120PubMedGoogle Scholar
  80. Samadi A, Carapetian J, Heidari R, Jafari M, Ghortapeh HA (2012a) Hairy root induction in Linum mucronatum ssp. mucronatum, an anti-tumor lignans producing plant. Not Bot Horti Agrobo 40(1):125–131Google Scholar
  81. Samadi A, Carapetian J, Zadeh MQ, Ghortapeh HA (2012b) Comparison of two culture media for breaking seed dormancy and germination improvement in four species of Linum L. Afr J Biotechnol 11(20):4699–4705Google Scholar
  82. Schmidt TJ, Hemmati S, Klaes M, Konuklugil B, Mohagheghzadeh A, Ionkova I, Fuss E, Alfermann AW (2010) Lignans in flowering aerial parts of Linum species: chemodiversity in the light of systematics and phylogeny. Phytochemistry 71(14–15):1714–1728PubMedGoogle Scholar
  83. Schmidt TJ, Klaes M, Sendker J (2012) Lignans in seeds of Linum species. Phytochemistry 82:89–99PubMedGoogle Scholar
  84. Seidel V, Windhövel J, Eaton G, Alfermann AW, Arroo RRJ, Medarde M, Petersen M, Woolley JG (2002) Biosynthesis of podophyllotoxin in Linum album cell cultures. Planta 215(6):1031–1039PubMedGoogle Scholar
  85. Shams-Ardakani M, Hemmati S, Mohagheghzadeh A (2005) Effect of elicitors on the enhancement of podophyllotoxin biosynthesis in suspension cultures of Linum album. DARU 13(2):56–60Google Scholar
  86. Smollny T, Wichers H, De Rijk T, Van Zwam A, Shasavari A, Alfermann AW (1992) Formation of lignans in suspension cultures of Linum album. Planta Med 58(7 suppl.):A622–A624Google Scholar
  87. Smollny T, Wichers H, Kalenberg S, Shahsavari A, Petersen M, Alfermann AW (1998) Accumulation of podophyllotoxin and related lignans in cell suspension cultures of L. album. Phytochemistry 48(6):975–979Google Scholar
  88. Soledade M, Pedras C, Zaharia IL (2000) Sinalbins A and B, phytoalexins from Sinapis alba: elicitation, isolation and synthesis. Phytochemistry 55(3):213–216Google Scholar
  89. Stöckigt J, Klischies M (1977) Biosynthesis of lignans. Part I. Biosynthesis of arctiin and phillyrin. Holzforschung 31(2):41–44Google Scholar
  90. Suzuki S, Umezawa T, Shimada M (1999) Stereochemical selectivity in secoisolariciresinol formation by cell free extract from Arctium lappa L. ripening seeds. Wood Res 86:37–38Google Scholar
  91. Umezawa T, Shimada M (1996) Enantiomeric composition of (−)-pinoresinol, (+)-matairesinol and (+)-wikstromol isolated from Wikstroemia sikokiana. Mokuzai Gakkaishi 42(2):180–185Google Scholar
  92. Umezawa T, Davin LB, Lewis NG (1991) Formation of lignans (−)-secoisolariciresinol and (−)-matairesinol with Forsythia intermedia cell-free extracts. J Biol Chem 266(16):10210–10217PubMedGoogle Scholar
  93. Umezawa T, Kuroda H, Isohata T, Higuchi T, Shimada M (1994) Enantioselective lignan synthesis by cell-free extracts of Forsythia koreana. Biosci Biotech Biochem 58(2):230–234Google Scholar
  94. van Furden B, Humburg A, Fuss E (2005) Influence of methyl jasmonate on podophyllotoxin and 6-methoxypodophyllotoxin accumulation in Linum album cell suspension cultures. Plant Cell Rep 24(5):312–317PubMedGoogle Scholar
  95. van Uden W, Pras N, Malingré TM (1990a) On the improvement of the podophyllotoxin production by phenylpropanoid precursor feeding to cell cultures of Podophyllum hexandrum Royle. Plant Cell Tissue Org Cult 23(3):217–224Google Scholar
  96. van Uden W, Pras N, Vossebeld EM, Mol JNM, Malingr TM (1990b) roduction of 5-methoxypodophyllotoxin in cell suspension cultures of Linum flavum L. Plant Cell Tissue Org Cult 20(2):81–87Google Scholar
  97. van Uden W, Pras N, Batterman S, Visser JF, Malingré TM (1991a) The accumulation and isolation of coniferin from a high-producing cell suspension of Linum flavum L. Planta 183(1):25–30PubMedGoogle Scholar
  98. van Uden W, Pras N, Homan B, Malingr TM (1991b) Improvement of the production of 5-methoxypodophyllotoxin using a new selected root culture of Linum flavum L. Plant Cell Tissue Org Cult 27(2):115–121Google Scholar
  99. van Uden W, Homan B, Woerdenbag HJ, Pras N, Malingre TM, Wichers HJ, Harkes M (1992) Isolation, purification, and cytotoxicity of 5-methoxypodophyllotoxin, a lignan from a root culture of Linum flavum. J Nat Prod 55(1):102–110PubMedGoogle Scholar
  100. van Uden W, Oeij H, Woerdenbag HJ, Pras N (1993) Glucosylation of cyclodextrin-complexed podophyllotoxin by cell cultures of Linum flavum L. Plant Cell Tissue Org Cult 34(2):169–175Google Scholar
  101. Vardapetyan HR, Kirakosyan AB, Oganesyan AA, Penesyan AR, Alfermann AW (2003) Effect of various elicitors on lignan biosynthesis in callus cultures of Linum austriacum. Russian J Plant Physiol 50(3):297–300Google Scholar
  102. Vasilev N, Ionkova I (2004) Lignan accumulation in cell cultures of Linum strictum ssp. strictum L. Acta Pharm 54(4):347–351PubMedGoogle Scholar
  103. Vasilev N, Momekov G, Zaharieva M, Konstantinov S, Bremner P, Heinrich M, Ionkova I (2005) Cytotoxic activity of a podophyllotoxin-like lignan from Linum tauricum Willd. Neoplasma 52(5):425–429PubMedGoogle Scholar
  104. Vasilev N, Elfahmi E, Bos R, Kayser O, Momekov G, Konstantinov S, Ionkova I (2006) Production of justicidin B, a cytotoxic arylnaphthalene lignan from genetically transformed root cultures of Linum leonii. J Nat Prod 69(7):1014–1017PubMedGoogle Scholar
  105. Vasilev N, Ebel R, Edrada R, Fuss E, Alfermann AW, Ionkova I, Petrova A, Repplinger M, Schmidt TJ (2008) Metabolic profiling of lignan variability in Linum species of section Syllinum native to Bulgaria. Planta Med 74(3):273–280PubMedGoogle Scholar
  106. von Heimendahl CBI, Schäfer KM, Eklund P, Sjöholm R, Schmidt TJ, Fuss E (2005) Pinoresinol–lariciresinol reductases with different stereospecificity from Linum album and Linum usitatissimum. Phytochemistry 66(11 spec iss.):1254–1263Google Scholar
  107. Wang Z et al (2012) The genome of flax (Linum usitatissimum) assembled de novo from short shotgun sequence reads. Plant J 72(3):461–473PubMedGoogle Scholar
  108. Wichers HJ, Harkes MP, Arroo RRJ (1990) Occurrence of 5-methoxypodophyllotoxin in plants, cell cultures and regenerated plants of Linum flavum. Plant Cell Tissue Org Cult 23(2):93–100Google Scholar
  109. Wink M, Alfermann AW, Franke R, Wetterauer B, Distl M et al (2005) Sustainable bioproduction of phytochemicals by plant in vitro cultures: anticancer agents. Plant Genetic Resour 3(2):90–100Google Scholar
  110. Woerdenbag HJ, van Uden W, Frijlink HW, Lerk CF, Pras N, Malingré TM (1990) Increased podophyllotoxin production in Podophyllum hexandrum cell suspension cultures after feeding coniferyl alcohol as a β-cyclodextrin complex. Plant Cell Rep 9(2):97–100PubMedGoogle Scholar
  111. Wu YM, Zhang HB, Zhao YH, Zhao JF, Chen JB, Li L (2007) A new and efficient strategy for the synthesis of podophyllotoxin and its analogues. Org Lett 9(7):1199–1202PubMedGoogle Scholar
  112. Xia ZQ, Costa MA, Proctor J, Davin LB, Lewis NG (2000) Dirigent-mediated podophyllotoxin biosynthesis in Linum flavum and Podophyllum peltatum. Phytochemistry 55(6):537–549PubMedGoogle Scholar
  113. Xia ZQ, Costa MA, Pélissier HC, Davin LB, Lewis NG (2001) Secoisolariciresinol dehydrogenase purification, cloning, and functional expression. J Biol Chem 276(16):12614–12623PubMedGoogle Scholar
  114. Yang Y, Shah J, Klessig DF (1997) Signal perception and transduction in plant defense responses. Genes Dev 11(13):1621–1639PubMedGoogle Scholar
  115. Yildiz M (2011) Evaluation of the effect of in vitro stress and competition on tissue culture response of flax. Biol Plantarum 55(3):541–544Google Scholar
  116. Yildiz M, Ozgen M (2004) The effect of a submersion pretreatment on in vitro explant growth and shoot regeneration from hypocotyls of flax (Linum usitatissimum). Plant Cell Tissue Org Cult 77(1):111–115Google Scholar
  117. Yildiz M, Ozcan S, Er C (2002) The effect of different explant sources on adventitious shoot regeneration in flax (Linum usitatissimum L.). Turk J Biol 26:37–40Google Scholar
  118. Yildiz M, Saglik C, Telci C, Day S, Ozat H (2010) The effect of drying and submersion pretreatment on adventitious shoot regeneration from hypocotyl explants of flax (Linum usitatissimum L.). Turk J Bot 34:323–328Google Scholar
  119. Yildiz M, Saglik C, Telci C, Erkilic EG (2011) The effect of in vitro competition on shoot regeneration from hypocotyl explants of Linum usitatissimum. Turk J Bot 35:211–218Google Scholar
  120. Yousefzadi M, Sharifi M, Behmanesh M, Ghasempour A, Moyano E, Palazon J (2010a) Salicylic acid improves podophyllotoxin production in cell cultures of Linum album by increasing the expression of genes related with its biosynthesis. Biotechnol Lett 32(11):1739–1743PubMedGoogle Scholar
  121. Yousefzadi M, Sharifi M, Behmanesh M, Moyano E, Bonfill M, Cusido RM, Palazon J (2010b) Podophyllotoxin: current approaches to its biotechnological production and future challenges. Eng Life Sci 10(4):281–292Google Scholar
  122. Yousefzadi M, Sharifi M, Chashmi NA, Behmanesh M, Ghasempour A (2010c) Optimization of podophyllotoxin extraction method from Linum album cell cultures. Pharm Biol 48(12):1421–1425PubMedGoogle Scholar
  123. Yousefzadi M, Sharifi M, Behmanesh M, Ghasempour A, Elisabeth M, Palazon J (2012) The effect of light on gene expression and podophyllotoxin biosynthesis in Linum album cell culture. Plant Physiol Biochem 56:41–46PubMedGoogle Scholar
  124. Zhao J, Davis LC, Verpoorte R (2005) Elicitor signal transduction leading to production of plant secondary metabolites. Biotechnol Adv 23(4):283–333PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • S. Malik
    • 1
  • O. Bíba
    • 1
    • 2
  • J. Grúz
    • 1
    • 2
  • R. R. J. Arroo
    • 3
  • M. Strnad
    • 1
    • 2
  1. 1.Faculty of Science, Centre of the Region Haná for Biotechnological and Agricultural ResearchPalacký UniversityOlomoucCzech Republic
  2. 2.Laboratory of Growth Regulators, Institute of Experimental Botany AS CRPalacký UniversityOlomoucCzech Republic
  3. 3.Leicester School of PharmacyDe Montfort UniversityLeicesterUK

Personalised recommendations