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Sustainable bioproduction of phytochemicals by plant in vitro cultures: anticancer agents

Published online by Cambridge University Press:  12 February 2007

Michael Wink ,
A. Wilhelm Alfermann ,
Rochus Franke ,
Bernhard Wetterauer ,
Melanie Distl ,
Jörg Windhövel ,
Oliver Krohn ,
Elisabeth Fuss ,
Hermann Garden  and
Abdolali Mohagheghzadeh
...Show all authors
Michael Wink*
Affiliation:
Institut für Pharmazie und Molekulare Biotechnologie, Universität Heidelberg, INF 364, 69120, Heidelberg, Germany
A. Wilhelm Alfermann
Affiliation:
Institut für Entwicklungs- und Molekularbiologie der Pflanzen, Universität Düsseldorf, Universitätsstr. 1, 40225, Düsseldorf, Germany
Rochus Franke
Affiliation:
Institut für Pharmazie und Molekulare Biotechnologie, Universität Heidelberg, INF 364, 69120, Heidelberg, Germany
Bernhard Wetterauer
Affiliation:
Institut für Pharmazie und Molekulare Biotechnologie, Universität Heidelberg, INF 364, 69120, Heidelberg, Germany
Melanie Distl
Affiliation:
Institut für Pharmazie und Molekulare Biotechnologie, Universität Heidelberg, INF 364, 69120, Heidelberg, Germany
Jörg Windhövel
Affiliation:
Institut für Entwicklungs- und Molekularbiologie der Pflanzen, Universität Düsseldorf, Universitätsstr. 1, 40225, Düsseldorf, Germany
Oliver Krohn
Affiliation:
Institut für Entwicklungs- und Molekularbiologie der Pflanzen, Universität Düsseldorf, Universitätsstr. 1, 40225, Düsseldorf, Germany
Elisabeth Fuss
Affiliation:
Institut für Entwicklungs- und Molekularbiologie der Pflanzen, Universität Düsseldorf, Universitätsstr. 1, 40225, Düsseldorf, Germany
Hermann Garden
Affiliation:
Institut für Entwicklungs- und Molekularbiologie der Pflanzen, Universität Düsseldorf, Universitätsstr. 1, 40225, Düsseldorf, Germany
Abdolali Mohagheghzadeh
Affiliation:
Department of Pharmacognosy, Faculty of Pharmacy, Shiraz University of Medical Sciences and Health Services, Shiraz, Iran
Eckart Wildi
Affiliation:
Rootec GmbH, 69123, Heidelberg, Germany
Peter Ripplinger
Affiliation:
Rootec GmbH, 69123, Heidelberg, Germany
*
*Corresponding author: E-mail: wink@uni-hd.de
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Abstract

Due to their complex structure with several chiral centres important anticancer agents are still extracted from plants and not synthesized chemically on a commercial scale. Sustainable bioproduction of the compounds of interest may be achieved by plant in vitro cultures. Undifferentiated callus and suspension cultures, which can be cultivated in large bioreactors easily, very often fail to accumulate the compounds of interest, whereas shoot and root cultures as well hairy roots normally produce the same compounds as in the appropriate organs. The production of anticancer compounds, such as the alkaloids vinblastine, vincristine, paclitaxel (Taxol®), camptothecin, or the lignan podophyllotoxin, by plant in vitro cultures is reviewed. Taxanes can be produced in bioreactors using cell suspensions of various Taxus species with good yields; presently paclitaxel is produced on a commercial scale by Phyton Biotech (Germany). Camptothecin has low yields in suspension cultures of Camptotheca acuminata or Nothapodytes foetida (0.0003–0.01%), but a good production (0.1–0.3% dry wt) in root and hairy root cultures of Ophiorrhiza pumila, O. mungos and C. acuminata. Podophyllotoxin can be produced in cell suspension and root as well as hairy root cultures of Podophyllum and various Linum species up to 130 mg/l (Linum album cell suspensions); its derivative 6-methoxypodophyllotoxin is accumulated in hairy roots of L. persicum up to about 500 mg/l. The in vitro production of dimeric indole alkaloids in Catharanthus roseus has failed so far both in undifferentiated and differentiated in vitro cultures. In cases where in vitro cultures show good yields, they can be employed in biotechnology for the sustainable production of valuable products.

Keywords

anticancer agentsbioproductioncamptothecinhairy rootsin vitro culturesphytochemicalspodophyllotoxinroot cultures
Type
Research Article
Information
Plant Genetic Resources , Volume 3 , Issue 2 , August 2005 , pp. 90 - 100
Copyright
Copyright © NIAB 2005

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References

Akcam-Oluk, E, Demiray, H and Gurel, E (2003) Alkaloid production from cell suspension cultures obtained from osmotic-stressed callus lines of Catharanthus roseus. Plant Cell Biotechnology and Molecular Biology 4: 91–94.Google Scholar
Baebler, S, Camloh, M, Kovac, M, Ravnikar, M and Zel, J (2002) Jasmonic acid stimulates taxane production in cell suspension culture of yew (Taxus × media). Planta Medica 68: 475–476.CrossRefGoogle Scholar
Bais, HP, Suresh, B and Raghavarao, KSMS (2002) Performance of hairy root cultures of Cichorium intybus L. in bioreactors of different configurations. In Vitro Cellular & Developmental Biology—Plant 38: 573–580.CrossRefGoogle Scholar
Bourgaud, F, Gravot, A, Milesi, S and Gontier, E (2001) Production of plant secondary metabolites: a historical perspective. Plant Science 161: 839–851.CrossRefGoogle Scholar
Ciddi, V and Shuler, ML (2000) Camptothecin from callus cultures of Nothapodytes foetida. Biotechnology Letters 22: 129–132.CrossRefGoogle Scholar
Cuello, JL, Walker, PN and Curtis, WR (2003 a) Design of ebb-and-flow bioreactor (EFBR) for immobilized ‘hairy root’ cultures: part I. Preliminary design models and culture parameters. Transactions of the ASAE (American Society of Agricultural Engineers) 46: 1457–1468.Google Scholar
Cuello, JL, Walker, PN and Curtis, WR (2003 b) Design of ebb-and-flow bioreactor (EFBR) for immobilized ‘hairy root’ cultures: part II. Growth studies and model verifications. Transactions of the ASAE (American Society of Agricultural Engineers) 46: 1469–1476.Google Scholar
De Luca, V and St. Pierre, B (2000) The cell and developmental biology of alkaloid biosynthesis. Trends in Plant Science 5: 168–173.CrossRefGoogle ScholarPubMed
Doran, PM (1997) Hairy Roots, Culture and Applications. Amsterdam: Harwood Academic PublishersGoogle Scholar
Du, W (2003) Towards new anticancer drugs: a decade of advances in synthesis of camptothecins and related alkaloids. Tetrahedron 59: 8649–8687.CrossRefGoogle Scholar
El-Sayed, M, Choi, YH, Frederich, M, Roytrakul, S and Verpoorte, R (2004) Alkaloid accumulation in Catharanthus roseus cell suspension cultures fed with stemmadenine. Biotechnology Letters 26: 793–798.CrossRefGoogle ScholarPubMed
Empt, U, Alfermann, AW, Pras, N and Petersen, M (2000) The use of plant cell cultures for the production of podophyllotoxin and related lignans. Journal of Applied Botany 74: 145–150.Google Scholar
Flores, HE, Hoy, MW and Pickard, JJ (1987) Secondary metabolites from root cultures. Trends in Biotechnology 5: 64–69.CrossRefGoogle Scholar
Fulzele, DP, Satdive, RK and Pol, BB (2001) Growth and production of camptothecin by cell suspension cultures of Nothapodytes foetida. Planta Medica 67: 150–152.CrossRefGoogle ScholarPubMed
Fuss, E (2003) Lignans in plant cell and organ cultures: an overview. Phytochemistry Reviews 2: 307–320.CrossRefGoogle Scholar
Garcia-Carbonero, R and Supko, JG (2002) Current perspectives on the clinical experience, pharmacology and continued development of the camptothecins. Clinical Cancer Research 8: 641–661.Google ScholarPubMed
Giri, A and Narasu, ML (2000) Transgenic hairy roots: recent trends and applications. Biotechnology Advances 18: 1–22.CrossRefGoogle ScholarPubMed
Hamill, JD, Parr, AJ, Rhodes, MJC, Robins, RJ and Walton, NJ (1987) New routes to plant secondary products. Bio/Technology 5: 800–804.Google Scholar
Harborne, JB (1993) Introduction to Ecological Biochemistry, 4th edn. London: Academic PressGoogle Scholar
Hvoslef-Eide, AK and Preil, W (2004) Liquid Culture Systems for In Vitro Plant Propagation. Heidelberg: SpringerGoogle Scholar
Hu, Y-M, Gan, F-Y, Lu, C-H, Ding, H-S and Shen, Y-M (2003) Productions of taxol and related taxanes by cell suspension cultures of Taxus yunnanensis. Acta Botanica Sinica 45: 373–378.Google Scholar
Huang, Z, Mu, Y, Zhou, Y, Chen, W, Xu, K, Yu, Z, Bian, Y and Yang, Q (1997) Transformation of Taxus brevifolia by Agrobacterium rhizogenes and taxol production in hairy root culture. Acta Botanica Yunnanica 19: 292–296.Google Scholar
Imbert, TF (1998) Discovery of podophyllotoxin. Biochimie 80: 207–222.CrossRefGoogle Scholar
Jeong, GT, Park, DH, Hwang, B and Woo, JC (2003) Comparison of growth characteristics of Panax ginseng hairy roots in various bioreactors. Applied Biochemistry and Biotechnology 105: 493–503.CrossRefGoogle ScholarPubMed
Kadkade, PG (1982) Growth and podophyllotoxin production in callus tissues of Podophyllum peltatum. Plant Science Letters 25: 107–115.CrossRefGoogle Scholar
Ketchum, REB, Rithner, CD, Qiu, D, Kim, YS, Williams, RM and Croteau, RB (2003) Taxus metabolomics: methyl jasmonate preferentially induces production of taxoids oxygenated at C-13 in Taxus × media cell cultures. Phytochemistry 62: 901–909.CrossRefGoogle Scholar
Kim, Y, Wyslouzil, BE and Weathers, PJ (2002) Secondary metabolism of hairy root cultures in bioreactors. In Vitro Cellular & Developmental Biology—Plant 38: 1–10.CrossRefGoogle Scholar
Lan, WZ, Qin, WM, Yu, LJ and Yang, X (2003) Hydrogen peroxide from the oxidative burst is not involved in the induction of taxol biosynthesis in Taxus chinensis cells. Zeitschrift für Naturforschung 58: 605–608.CrossRefGoogle Scholar
Lerchen, H-G (2002) Milestones in camptothecin research. Drugs of the Future 27: 869–878.CrossRefGoogle Scholar
López-Meyer, M, Nessler, CL and McKnight, TD (1994) Sites of accumulation of the antitumour alkaloid camptothecin in Camptotheca acuminata. Planta Medica 60: 558–560.CrossRefGoogle Scholar
Lorence, A and Nessler, CL (2004) Camptothecin, over four decades of surprising findings. Phytochemistry 65: 2735–2749.CrossRefGoogle ScholarPubMed
Lorence, A, Medina-Bolivar, F and Nessler, CL (2004) Camptothecin and 10-hydroxycamptothecin from Camptotheca acuminata hairy roots. Plant Cell Reports 22: 437–441.CrossRefGoogle ScholarPubMed
Loyola-Vargas, VM and Miranda-Ham, ML (1995) Root culture as a source of secondary economic importance. Recent Advances in Phytochemistry 29: 217–248.Google Scholar
Luo, J and Mei, X-G (2002) Taxol production in suspension cultures of Taxus chinensis as affected by the combination of nutrient feed with dissolved oxygen control. Acta Botanica Sinica 44: 1286–1290.Google Scholar
Mann, J (1992) Murder, Magic and Medicine. London: Oxford University PressGoogle Scholar
Mei, X, Lu, M, Yu, L and Hu, D (1996) Kinetics of taxol biosynthesis in bioreactors. Medicinal Chemistry Research 6: 256–263.Google Scholar
Mohagheghzadeh, A, Hemmati, S, Mehregan, I and Alfermann, AW (2003) Linum persicum: lignans and placement in Linaceae. Phytochemistry Reviews 2: 363–369.CrossRefGoogle Scholar
Navia-Osorio, A, Garden, H, Cusido, RM, Palazon, J, Alfermann, AW and Pinol, MT (2002) Taxol ® and baccatin III production in suspension cultures of Taxus baccata and Taxus wallichiana in an airlift bioreactor. Journal of Plant Physiology 159: 97–102.CrossRefGoogle Scholar
Palazon, J, Cusido, RM, Gonzalo, J, Bonfill, M, Morales, C and Pinol, MT (1998) Relation between the amount of rolC gene product and indole alkaloid accumulation in Catharanthus roseus transformed root cultures. Journal of Plant Physiology 153: 712–718.CrossRefGoogle Scholar
Palazon, J, Mallol, A, Eibl, R, Lettenbauer, C, Cusido, RM and Pinol, MT (2003) Growth and ginsenoside production in hairy root cultures of Panax ginseng using a novel bioreactor. Planta Medica 69: 344–349.CrossRefGoogle ScholarPubMed
Pestchanker, LJ, Roberts, SC and Shuler, ML (1996) Kinetics of taxol production and nutrient use in suspension cultures of Taxus cuspidata in shake flasks and a Wilson-type bioreactor. Enzyme and Microbial Technology 19: 256–260.CrossRefGoogle Scholar
Petersen, M and Alfermann, AW (2001) The production of cytotoxic lignans by plant cell cultures. Applied Microbiology and Biotechnology 55: 135–142.CrossRefGoogle ScholarPubMed
Ramachandra, R and Ravishankar, GA (2002) Plant cell cultures: chemical factories of secondary metabolites. Biotechnology Advances 20: 101–153.CrossRefGoogle Scholar
Ramakrishnan, D and Curtis, WR (2004) Trickle-bed root culture bioreactor design and scale-up: growth, fluid-dynamics, and oxygen mass transfer. Biotechnology and Bioengineering 88: 248–260.CrossRefGoogle ScholarPubMed
Roberts, MF and Wink, M (1998) Alkaloids—Biochemistry, Ecological Functions and Medical Applications. New York: PlenumGoogle Scholar
Roja, G and Heble, MT (1994) The quinone alkaloids and 9-methoxycamptothecin from tissue cultures and mature trees of Nothapodytes foetida. Phytochemistry 36: 65–66.CrossRefGoogle Scholar
Saito, K, Sudo, H, Yamazaki, M, Koseki-Nakamura, M, Kitajima, M, Takayama, H and Aimi, N (2001) Feasible production of camptothecin by hairy root culture of Ophiorrhiza pumila. Plant Cell Reports 20: 267–271.CrossRefGoogle Scholar
Sakato, K, Tanaka, H, Mukai, N and Misawa, M (1974) Isolation and identification of camptothecin from cells of Camptotheca acuminata suspension cultures. Agricultural and Biological Chemistry 38: 217–218.CrossRefGoogle Scholar
Schröder, G, Unterbusch, E, Kaltenbach, M, Schmidt, J, Strack, D De, Luca, V, Schröder, J (1999) Light-induced cytochrome P450-dependent enzyme in indole alkaloid biosynthesis: tabersonine 16-hydroxylase. FEBS Letters 458: 97–102.CrossRefGoogle ScholarPubMed
Sehrawat, AR, Uppal, S and Punia, A (2002) Effect of plant growth regulators on relative growth rate, multiple shoot formation and alkaloid accumulation in Catharanthus roseus (L.) G. Don. Indian Journal of Genetics and Plant Breeding 62: 61–64.Google Scholar
Seigler, DS (1998) Plant Secondary Metabolism. Boston: KluwerCrossRefGoogle Scholar
Sevon, N and Oksman-Caldentey, K-M (2002) Agrobacterium rhizogenes -mediated transformation: root cultures as a source of alkaloids. Planta Medica 68: 859–868.CrossRefGoogle ScholarPubMed
Sharma, TR, Singh, BM, Sharma, NR and Chauhan, RS (2000) Identification of high podophyllotoxin producing biotypes of Podophyllum hexandrum Royle from North-West Himalaya. Journal of Plant Biochemistry and Biotechnology 9: 49–51.CrossRefGoogle Scholar
Shuler, M (2001) Bioprocess Engineering: Basic Concepts, 2nd edn. Englewood Cliffs, NJ: Prentice HallGoogle Scholar
Smollny, T, Wichers, H, Kalenberg, S, Shahsavari, A, Petersen, M and Alfermann, AW (1998) Accumulation of podophyllotoxin and related lignans in cell suspension cultures of Linum album. Phytochemistry 48: 975–979.CrossRefGoogle Scholar
Son, SH, Choi, SM, Lee, YH, Choi, KB, Yun, SR, Kim, JK, Park, HJ, Kwon, OW, Noh, EW, Seon, JH and Park, YG (2000) Large-scale growth and taxane production in cell cultures of Taxus cuspidata (Japanese yew) using a novel bioreactor. Plant Cell Reports 19: 628–633.CrossRefGoogle ScholarPubMed
Sudo, H, Yamakawa, T, Yamazaki, M, Aimi, N and Saito, K (2002) Bioreactor production of camptothecin by hairy root cultures of Ophiorrhiza pumila. Biotechnology Letters 24: 359–363.CrossRefGoogle Scholar
Thengane, SR, Kulkarni, DK, Shrikhande, VA, Joshi, SP, Sonawane, KB and Krishnamurthy, KV (2003) Influence of medium composition on callus induction and camptothecin accumulation in Nothapodytes foetida. Plant Cell, Tissue and Organ Culture 72: 247–251.CrossRefGoogle Scholar
Tikhomiroff, C and Jolicoeur, M (2002) Screening of Catharanthus roseus secondary metabolites by high-performance liquid chromatography. Journal of Chromatography A 955: 87–93.CrossRefGoogle ScholarPubMed
van Hengel, AJ, Harkes, MP, Wichers, HJ, Hesselink, PGM and Buitelaar, RM (1992) Characterisation of callus formation and camptothecin production by cell lines of Camptotheca acuminata. Plant Cell, Tissue and Organ Culture 28: 11–18.CrossRefGoogle Scholar
van Wyk, B-E and Wink, M (2004) Medicinal Plants of the World. Pretoria: BrizaGoogle Scholar
Verpoorte, R, Contin, A and Memelink, J (2002) Biotechnology for the production of plant secondary metabolites. Phytochemical Review 1: 13–25.CrossRefGoogle Scholar
Wagner, F and Vogelmann, H (1977) Cultivation of plant tissue cultures in bioreactors and formation of secondary metabolites. In: Barz, W, Reinhard, E and Zenk, MH (eds) Plant Tissue Culture and its Bio-technological Application. New York: Springer pp. 245–252CrossRefGoogle Scholar
Walton, NJ, Alfermann, AW and Rhodes, MJC (1999) Production of secondary metabolites in cell and differentiated organ cultures. In: Wink, M (ed.) Function of Plant Secondary Metabolites and their Exploitation in Biotechnology, Vol. 3. Annual Plant Reviews, Sheffield: Sheffield Academic Press and CRC Press, pp. 311–345Google Scholar
Wang, C, Wu, J and Mei, X (2001) Enhancement of Taxol production and excretion in Taxus chinensis cell culture by fungal elicitation and medium renewal. Applied Microbiology and Biotechnology 55: 404–410.CrossRefGoogle ScholarPubMed
Wildi, E, Wildi, R and, Ripplinger, P (2003) Device for cultivating plant or animal tissue cultures. US Patent Application Pbl. No. US /0129743 A1.Google Scholar
Wink, M (1987 a) Why do lupin cell cultures fail to produce alkaloids in large quantities? Plant Cell, Tissue and Organ Culture 8: 103–111.CrossRefGoogle Scholar
Wink, M (1987 b) Physiology of the accumulation of secondary metabolites with special reference to alkaloids. In: Constabel, F and Vasil, I (eds) Cell Culture and Somatic Cell Genetics of Plants, Vol. 4. Cell Culture in Phytochemistry New York: Academic Press 17–41Google Scholar
Wink, M (1988) Plant breeding: importance of plant secondary metabolites for protection against pathogens and herbivores. Theoretical and Applied Genetics 75: 225–233.CrossRefGoogle Scholar
Wink, M (1993) Allelochemical properties and the raison d'être of alkaloids. In: Cordell, GThe Alkaloids, Vol. 43. Orlando, FL: Academic Press 1–118Google Scholar
Wink, M (1999 a) Biochemistry of Plant Secondary Metabolism, Vol. 2. Annual Plant Reviews. Sheffield: Sheffield Academic Press and CRC PressGoogle Scholar
Wink, M (1999 b) Function of Plant Secondary Metabolites and their Exploitation in Biotechnology, Vol. 3. Annual Plant Reviews. Sheffield: Sheffield Academic Press and CRC PressGoogle Scholar
Wink, M (2000) Interference of alkaloids with neuroreceptors and ion channels. In: Atta-Ur-Rahman, (ed.) Bioactive Natural Products, Vol. 11. Amsterdam: Elsevier. 3–129Google Scholar
Wu, J and Ge, X (2004) Oxidative burst, jasmonic acid biosynthesis, and Taxol production induced by low-energy ultrasound in Taxus chinensis cell suspension cultures. Biotechnology and Bioengineering 85: 714–721.CrossRefGoogle ScholarPubMed
Wu, J and Lin, L (2003) Enhancement of taxol production and release in Taxus chinensis cell cultures by ultrasound, methyl jasmonate and in situ solvent extraction. Applied Microbiology and Biotechnology 62: 151–155.CrossRefGoogle ScholarPubMed
Wysokinska, H and Chmiel, A (1997) Transformed root cultures for biotechnology. Acta Biotechnologica 17: 131–159.CrossRefGoogle Scholar
Yamazaki, Y, Sudo, H, Yamazaki, M, Aimi, N and Saito, K (2003 a) Camptothecin biosynthetic genes in hairy roots of Ophiorrhiza pumila: cloning, characterization and differential expression in tissues and by stress compounds. Plant Cell Physiology 44: 395–403.CrossRefGoogle ScholarPubMed
Yamazaki, Y, Urano, A, Sudo, H, Kitajima, M, Takayama, H, Yamazaki, M, Aimi, N and Saito, K (2003 b) Metabolic profiling of alkaloids and strictosidine synthase activity in camptothecin producing plants. Phytochemistry 62: 461–470.CrossRefGoogle Scholar
Yuan, Y-J, Li, J-C, Ge, Z-Q and Wu, J-C (2002) Superoxide anion burst and taxol production induced by Ce4+ in suspension cultures of Taxus cuspidata. Journal of Molecular Catalysis B Enzymatic 18: 251–260.CrossRefGoogle Scholar
Zhao, Z, Xu, Y, Qian, Z, Tian, W, Qian, X and Zhong, J-J (2004) Novel fluoro- and hydroxyl-containing jasmonate derivatives as highly efficient elicitors in suspension cultures of Taxus chinensis. Bioorganic & Medicinal Chemistry Letters 14: 4755–4758.CrossRefGoogle ScholarPubMed
Zhong, JJ (2003) Biochemical engineering of the production of plant-specific secondary metabolites by cell suspension cultures. Advances in Biochemical Engineering/Biotechnology 72: 1–26.Google Scholar
Zunino, F and Pratesi, G (2004) Camptothecins in clinical development. Expert Opinion Investigating Drugs 13: 269–272.CrossRefGoogle ScholarPubMed