Skip to main content
SpringerLink
Log in

Biosynthesis and biotechnological production of anti-cancer drug Camptothecin

  • Published:
Phytochemistry Reviews Aims and scope Submit manuscript

Abstract

Camptothecin (CPT) is a kind of modified monoterpene indole alkaloid firstly identified from woody plant Camptotheca acuminata, and its semisynthetic CPT analogs irinothecan and topothecan are clinically used for the treatment of various cancers throughout the world. However, the extraction of CPT from limited natural CPT-producing plant resources couldn’t meet the rapidly increasing market need. The development of plant metabolic engineering provides one alternative way to increase CPT yield by genetic manipulation, which relies on in-depth understanding of the CPT biosynthesis pathway. Several attempts have been also made to obtain CPT by biotechnological approaches such as cell suspensions, endophytic fungi, hairy roots, elicitation as well as metabolic engineering in the past decade. Here, recent advances in knowledge of biosynthesis of CPT, gene isolation, molecular regulation, production improvement and biotechnological methods are summarized and future perspectives are also discussed in this review.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Aimi N, Nishimura M, Miwa A, Hoshino H, Sakai S, Haginiwa J (1989) Pumiloside and deoxypumiloside; plausible intermediates of camptothecin biosynthesis. Tetrahedron Lett 30:4991–4994

    Article  CAS  Google Scholar 

  • Amna T, Puri SC, Verma V, Sharma JP, Khajuria RK, Musarrat J, Spiteller M, Qazi GN (2006) Bioreactor studies on the endophytic fungus Entrophospora infrequens for the production of an anticancer alkaloid camptothecin. Can J Microbiol 52(3):189–196

    Article  CAS  PubMed  Google Scholar 

  • Arisawa M, Gunasekera SP, Cordell GA, Farnsworth NR (1981) Plant anticancer agents XXI constituents of Merrilliodendron megacarpum. Planta Med 43:404–407

    Article  CAS  PubMed  Google Scholar 

  • Asano T, Watase I, Sudo H, Kitajima M, Takayama H, Aimi N, Yamazaki M, Saito K (2004) Camptothecin production by in vitro cultures of Ophiorrhiza liukiuensis and O. kuroiwai. Plant Biotechnol 21(4):275–281

    Article  CAS  Google Scholar 

  • Asano T, Kobayashi K, Kashihara E, Sudo H, Sasaki R, Iijima Y, Aoki K, Shibata D, Saito K, Yamazaki M (2013) Suppression of camptothecin biosynthetic genes results in metabolic modification of secondary products in hairy roots of Ophiorrhiza pumila. Phytochemistry 91:128–139

    Article  CAS  PubMed  Google Scholar 

  • Aule O, Furholz A, Chang HS, Zhu T, Wang X, Heifetz PB, Gruissem W, Markus LB (2003) Crosstalk between cytosolic and plastidial pathways of isoprenoid biosynthesis in Arabidopsis thaliana. Proc Natl Acad Sci USA 100:6866–6871

    Article  Google Scholar 

  • Beegum AS, Martin KP, Zhang CL, Nishitha IK, Ligimol SA, Madhusoodanan PV (2007) Organogenesis from leaf and internode explants of Ophiorrhiza prostrata, an anticancer drug (camptothecin) producing plant. Electronic J Biotechnol 10(1):114–123

    Article  Google Scholar 

  • Burnett RT, Maldonado-Mendoza IE, Mcknight TD, Nessler CL (1993) Expression of a 3-hydroxy-3-methylglutaryl coenzyme a reductase cene from Camptotheca acuminata is differentially regulated by wounding and methyl jasmonate. Plant Physiol 103:41–48

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Canel C, Lopes-Cardoso MI, Whitmer S (1998) Effects of overexpression of strictosidine synthase and tryptophan decarboxylase on alkaloid production by cell cultures of Catharanthus roseus. Planta 205:414–419

    Article  CAS  PubMed  Google Scholar 

  • Chandra S (2012) Endophytic fungi: novel sources of anticancer lead molecules. Appl Microbiol Biotechnol 95(1):47–59

    Article  CAS  PubMed  Google Scholar 

  • Collu G, Alonso-García A, van Der Heijden R, Verpoorte R (2002) Activity of the cytochrome P450 enzyme geraniol-10-hydroxylase and alkaloid production in plant cell cultures. Plant Sci 162:165–172

    Article  CAS  Google Scholar 

  • Crawford IP (1989) Evolution of a biosynthetic pathway: the tryptophan paradigm. Annu Rev Microbiol 43:567–600

    Article  CAS  PubMed  Google Scholar 

  • Cui LJ, Ni XL, Ji Q, Teng XJ, Yang YR, Wu C, Zekria D, Zhang DS, Kai GY (2015) Co-overexpression of geraniol-10-hydroxylase and strictosidine synthase improves anti-cancer drug camptothecin accumulation in Ophiorrhiza pumila. Sci Rep 5:8227

    Article  PubMed Central  PubMed  Google Scholar 

  • De Luca V, Marineau C, Brisson N (1989) Molecular cloning and analysis of a cDNA encoding a plant tryptophan decarboxylase: comparison with animal DOPA decarboxylases. Proc Natl Acad Sci USA 86:2582–2586

    Article  PubMed Central  PubMed  Google Scholar 

  • Ding X, Liu K, Deng B, Chen W, Li W, Liu F (2013) Isolation and characterization of endophytic fungi from Camptotheca acuminata. World J Microbiol Biotechnol 29(10):1831–1838

  • Fujimoto T, Tomitaka Y, Abe H, Tsuda S, Futai K, Mizukubo T (2011) Expression profile of jasmonic acid-induced genes and the induced resistance against the root-knot nematode (Meloidogyne incognita) in tomato plants (Solanum lycopersicum) after foliar treatment with methyl jasmonate. J Plant Physiol 168(10):1084–1097

  • Fulzele DP, Satdive RK (2005) Comparison of techniques for the extraction of the anti-cancer drug camptothecin from Nothapodytes foetida. J Chromatogr A 1063(1–2):9–13

    Article  CAS  PubMed  Google Scholar 

  • Georgiev M, Agostini E, Ludwig-Müller J, Xu J (2012) Genetically transformed roots: from plant disease to biotechnology. Trends Biotechnol 30:528–537

    Article  CAS  PubMed  Google Scholar 

  • Govindachari TR, Viswanathan N (1972) Alkaloids of Mappia foetida. Phytochemistry 11:3529–3531

    Article  CAS  Google Scholar 

  • Gu Q, Song DF, Zhang H, Zhu MY (2006) Effects of Cu2+ on biosynthesis of camptothecin in cell cultures of Camptotheca acuminata. Sheng Wu Gong Cheng Xue Bao 22(4):624–628

    CAS  PubMed  Google Scholar 

  • Gunasekera SP, Badawi MM, Cordell GA, Farnsworth NR, Chitnis M (1979) Plant anticancer agents X. Isolation of camptothecin and 9-methoxycamptothecin from Ervatamia heyneana. J Nat Prod 42:475–477

    Article  CAS  PubMed  Google Scholar 

  • Gurudatt PS, Priti V, Shweta S, Ramesha BT, Ravikanth G, Vasudeva R, Amna T, Deepika S, Ganeshaiah KN, Shaanker RU, Puri S, Qazi GN (2010) Attenuation of camptothecin production and negative relation between hyphal biomass and camptothecin content in endophytic fungal strains isolated from Nothapodytes nimmoniana Grahm (Icacinaceae). Curr Sci 98:1006–1010

  • Hao XL, Shi M, Cui LJ, Xu C, Zhang YJ, Kai GY (2015) Effects of methyl jasmonate and salicylic acid on the tanshinone production and biosynthetic genes expressionin transgenic Salviamiltiorrhiza hairy roots. Biotech Appl Biochem 62(1):24–31

    Article  CAS  Google Scholar 

  • Herrmann KM, Weaver LM (1999) The shikimate pathway. Annu Rev Plant Physiol Plant Mol Biol 50:473–503

    Article  CAS  PubMed  Google Scholar 

  • Hsiang YH, Hertzberg R, Hecht S, Liu LF (1985) Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem 260(27):14873–14878

    CAS  PubMed  Google Scholar 

  • Hsieh MH, Goodman HM (2005) The Arabidopsis IspH homolog is involved in the plastid nonmevalonate pathway of isoprenoid biosynthesis. Plant Physiol 138(2):641–653

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Irmler S, Schröder G, St-Pierre B, Crouch NP, Hotze M, Schmidt J, Strack D, Matern U, Schröder J (2000) Indole alkaloid biosynthesis in Catharanthus roseus: new enzyme activities and identification of cytochrome P450 CYP72A1 as secologanin synthase. Plant J 24(6):797–804

    Article  CAS  PubMed  Google Scholar 

  • Kai GY, Miao ZQ, Zhang L, Zhao DL, Liao ZH, Sun XF, Zhao LX, Tang KX (2006) Molecular cloning and expression analyses of a new gene encoding 3-hydroxy-3-methylglutaryl-CoA synthase from Taxusx media. Biol Plantarum 50(3):359–366

    Article  CAS  Google Scholar 

  • Kai GY, Dai LM, Mei XY, Zheng JG, Wang W, Lu Y, Qian ZY, Zhou GY (2008) In vitro plant regeneration from leaf explants of Ophiorrhiza japonica. Biol Plantarum 52(3):557–560

    Article  CAS  Google Scholar 

  • Kai GY, Xu H, Zhou CC, Liao P, Xiao JB, Luo XQ, You LJ, Zhang L (2011a) Metabolic engineering tanshinone biosynthetic pathway in Salvia miltiorrhiza hairy root cultures. Metab Eng 13(3):319–327

    Article  CAS  PubMed  Google Scholar 

  • Kai GY, Yang S, Luo XQ, Zhou WT, Fu XQ, Zhang A, Zhang Y, Xiao JB (2011b) Co-expression of AaPMT and AaTRI effectively enhances the yields of tropane alkaloids in Anisodus acutangulus hairy roots. BMC Biotechnol 11:43

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kai GY, Ji Q, Lu Y, Qian ZY, Cui LJ (2012a) Expression of Monstera deliciosa agglutinin gene (mda) in tobacco confers resistance to peach-potato aphids. Integr Biol 4(8):937–944

    Article  CAS  Google Scholar 

  • Kai GY, Zhang A, Guo YY, Li L, Cui LJ, Luo XQ, Liu C, Xiao JB (2012b) Enhancing the production of tropane alkaloids in transgenic Anisodus acutangulus hairy root cultures by over-expressing tropinone reductase I and hyoscyamine-6b-hydroxylase. Mol BioSyst 8(11):2883–2890

    Article  CAS  PubMed  Google Scholar 

  • Kai GY, Liao P, Xu H, Wang J, Zhou CC, Zhou W, Qi YP, Xiao JB, Wang YL, Zhang L (2012c) Molecular mechanism of elicitor-induced tanshinone accumulation in Salvia miltiorrhiza hairy root cultures. Acta Physiol Plant 34(4):1421–1433

    Article  CAS  Google Scholar 

  • Kai GY, Yang S, Zhang Y, Luo XQ, Fu XQ, Zhang A, Xiao JB (2012d) Effects of different elicitors on yield of tropane alkaloids in hairy roots of Anisodus acutangulus. Mol Biol Rep 39(2):1721–1729

    Article  CAS  PubMed  Google Scholar 

  • Kai GY, Li SS, Wang W, Lu Y, Wang J, Liao P, Cui LJ (2013) Molecular cloning and expression analysis of a new gene encoding 3-hydroxy-3-methylglutaryl-CoA synthase from Camptotheca acuminata. Russ J Plant Physiol 60(1):131–138

    Article  CAS  Google Scholar 

  • Kai GY, Teng XJ, Cui LJ, Li SS, Hao XL, Shi M, Yan B (2014) Effect of three plant hormone elicitors on the camptothecin accumulation and gene transcript profiling in Camptotheca acuminata seedlings. Int J Sci 3(1):86–95

    Google Scholar 

  • Kitajima M, Fischer U, Nakamura M, Ohsawa M, Ueno M, Takayama H, Unger M, Stöckigt J, Aimi N (1998) Anthraquinones from Ophiorrhiza pumila tissue and cell cultures. Phytochemistry 48:107–111  

  • Kusari S, Zühlke S, Spiteller M (2009) An endophytic fungus from Camptotheca acuminata that produces camptothecin and analogues. J Nat Prod 72(1):2–7

    Article  CAS  PubMed  Google Scholar 

  • Kutchan TM (1989) Expression of enzymatically active cloned strictosidine synthase from the higher plant Rauvolfia serpentine in Escherichia coli. FEBS Lett 257:127–130

    Article  CAS  PubMed  Google Scholar 

  • Kutchan TM (1995) Alkaloid biosynthesis: the basis for metabolic engineering of medicinal plants. Plant Cell 7:1059–1070

    PubMed Central  CAS  PubMed  Google Scholar 

  • Li L, Wang J, Wang W, Lu Y, Wang YL, Zhou GY, Kai GY (2008) Optimization of induction and culture conditions and tropane alkaloid production in hairy roots of Anisodus acutangulus. Biotechnol Bioproc E 13:606–612

    Article  CAS  Google Scholar 

  • Liao P, Zhou W, Zhang L, Wang J, Yan XM, Zhang Y, Zhang R, Li L, Zhou GY, Kai GY (2009) Molecular cloning, characterization and expression analysis of a new gene encoding 3-hydroxy-3-methylglutaryl coenzyme A reductase from Salvia miltiorrhiza. Acta Physiol Plant 31(3):565–572

    Article  CAS  Google Scholar 

  • Liu JJ, Liu WD, Yang HZ, Zhang Y, Fang ZG, Liu PQ, et al (2010) Inactivation of PI3k/Akt signaling pathway and activation of caspase-3 are involved in tanshinone I-induced apoptosis in myeloid leukemia cells in vitro. Ann Hematol 89:1089–1097

  • Liu Z, Carpenter SB, Bourgeois WJ, Yu Y, Constantin RJ, Falcon MJ, Adams JC (1998) Variations in the secondary metabolite camptothecin in relation to tissue age and season in Camptotheca acuminata. Tree Physiol 18(4):265–270

    Article  CAS  PubMed  Google Scholar 

  • Lois LM, Rodriguez-Concepción M, Gallego F, Campos N, Boronat A (2000) Carotenoid biosynthesis during tomato fruit development:regulatory role of 1-deoxy-D-xylulose 5-phosphate synthase. Plant J 22:503–513

    Article  CAS  PubMed  Google Scholar 

  • López-Meyer M, Nessler CL (1997) Tryptophan decarboxylase is encoded by two autonomously regulated genes in Camptotheca acuminata which are differentially expressed during development and stress. Plant J 11(6):1167–1175

    Article  PubMed  Google Scholar 

  • Lopez-Meyer M, Nessler CL, McKnight TD (1994) Sites of accumulation of antitumor alkaloid camptothecin in Camptotheca acuminata. Planta Med 60:558–560

    Article  CAS  PubMed  Google Scholar 

  • Lorence A, Nessler CL (2004) Molecules of interest—camptothecin, over four decades of surprising findings. Phytochemistry 65:2735–2749

    Article  CAS  PubMed  Google Scholar 

  • Lorence A, Medina-Bolivar F, Nessler CL (2004) Camptothecin and 10-hydroxycamptothecin from Camptotheca acuminata hairy roots. Plant Cell Rep 22:437–441

    Article  CAS  PubMed  Google Scholar 

  • Lu H, McKnight TD (1999) Tissue-specific expression of the betasubunit of tryptophan synthase in Camptotheca acuminata, an indole alkaloid-producing plant. Plant Physiol 120:43–52

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lu H, Gorman E, McKnight TD (2005) Molecular characterization of two anthranilate synthase alpha subunit genes in Camptotheca acuminata. Planta 221(3):352–360

    Article  CAS  PubMed  Google Scholar 

  • Lu Y, Wang HS, Wang W, Qian ZY, Li L, Wang J, Zhou GY, Kai GY (2009) Molecular characterization and expression analysis of a new cdna encoding strictosidine synthase from Ophiorrhiza japonica. Mol Biol Rep 36(7):1845–1852

    Article  CAS  PubMed  Google Scholar 

  • Luo XQ, Wen SQ, Ni XN, Wang XY, Fu XQ, Xiao JB, Kai GY (2012) The effects of different elicitors on the production of tropane alkaloids and the expression of key enzyme genes in Anisodus acutangulus plant. Biologia 67(2):352–359

    Article  CAS  Google Scholar 

  • Ma L (2007) Callus induction and cultivation of Camptotheca acuminata. Zhongguo Zhong Yao Za Zhi 32(13):1273–1276

    PubMed  Google Scholar 

  • Mahmoud SS, Croteau RB (2001) Metabolic engineering of essential oil yield and composition in mint by altering expression of deoxyxylulose phosphate reductoisomerase and menthofuran synthase. Proc Natl Acad Sci USA 98:8915–8920

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Maldonado-Mendoza IE, Vincent RM, Nessler CL (1997) Molecular characterization of three differentially expressed members of the Camptotheca acuminata 3-hydroxy-3-methylglutaryl CoA reductase (HMGR) gene family. Plant Mol Biol 34:781–790

    Article  CAS  PubMed  Google Scholar 

  • McKnight TD, Roessner CA, Devagupta R, Scott AI, Nessler CL (1990) Nucleotide sequence of a cDNA encoding the vacuolar protein strictosidine synthase from Catharanthus roseus. Nucleic Acids Res 18:4939

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Min C,Wang X (2009) Isolation and identification of the 10-hydroxycamptothecin-producing endophytic fungi from Camptotheca acuminata Decne. Acta Bot Boreal Occident Sin 29(3): 614–617

  • Ni XL, Wen SQ, Wang W, Wang XY, Xu H, Kai GY (2011) Enhancement of camptothecin production in Camptotheca acuminata hairy roots by overexpressing ORCA3 gene. J App Pharm Sci 1(8):85–88

    Google Scholar 

  • Pan X, Chen M, Liu Y, Wang Q, Zeng L, Li L, Liao Z (2008)A new isopentenyl diphosphate isomerase gene from Camptotheca acuminata: cloning, characterization andfunctional expression in Escherichia coli. DNA Seq 19(2):98–105

  • Pan, Q, Wang Q, Yuan F, Xing S, Zhao J, Choi YH, Verpoorte R, Tian Y, Wang G, Tang K (2012) Overexpression of ORCA3 and G10H in Catharanthus roseus plants regulated alkaloid biosynthesis and metabolism revealed by NMR-metabolomics. PLoS One 7(8):e43038

  • Pi Y, Jiang K, Hou R, Gong Y, Lin J, Sun X, Tang K (2010) Examination of camptothecin and 10-hydroxycamptothecin in Camptotheca acuminata plant and cell culture, and the affected yields under several cell culture treatments. Biocell 34(3):139–143

  • Pu X, Qu X, Chen F, Bao J, Zhang G, Luo Y (2013) Camptothecin-producing endophytic fungus Trichoderma atroviride LY357: isolation, identification, and fermentation conditions optimization for camptothecin production. Appl Microbiol Biotechnol 97(21):9365–9375

    Article  CAS  PubMed  Google Scholar 

  • Puri SC, Verma V, Amna T, Qazi GN, Spiteller M (2005) An endophytic fungus from Nothapodytes foetida that produces camptothecin. J Nat Prod 68(12):1717–1719

    Article  CAS  PubMed  Google Scholar 

  • Rehman S, Shawl AS, Verma V, Kour A, Athar M, Andrabi R, Sultan P, Qazi GN (2008) An endophytic Neurospora sp. from Nothapodytes foetida producing camptothecin. Prikl Biokhim Mikrobiol 44(2):225–231

  • Rehman S, Shawl AS, Kour A, Sultan P, Ahmad K, Khajuria R, Qazi GN (2009) Comparative studies and identification of camptothecin produced by an endophyte at shake flask and bioreactor. Nat Prod Res 23:1050–1057  

  • Saito K, Sudo H, Yamazaki M, Koseki-Nakamura M, Kitajima M, Takayama H, Aimi N (2001) Feasible production of camptothecin by hairy root culture of Ophiorrhiza pumila. Plant Cell Rep 20:267–271

    Article  CAS  Google Scholar 

  • Sakato K, Tanaka H, Mukai N, Misawa M (1974) Isolation and identification of camptothecin from cells of Camptotheca acuminata suspension cultures. Agric Biol Chem 38:217–218

    Article  CAS  Google Scholar 

  • Shi M, Luo XQ, Ju GH, Yu XH, Hao XL, Huang Q, Xiao JB, Cui LJ, Kai GY (2014) Increased accumulation of the cardio-cerebrovascular disease treatment drug tanshinone in Salvia miltiorrhiza hairy roots by the enzymes 3-hydroxy-3-methylglutaryl CoA reductase and 1-deoxy-D-xylulose 5-phosphate reductoisomerase. Funct Integr Genomic 14(3):603–615

    Article  CAS  Google Scholar 

  • Shweta S, Zuehlke S, Ramesha BT, Priti V, Mohana Kumar P, Ravikanth G, Spiteller M, Vasudeva R, Uma Shaanker R (2010) Endophytic fungal strains of Fusarium solani, from Apodytes dimidiata E. Mey. ex Arn (Icacinaceae) produce camptothecin, 10-hydroxycamptothecin and 9-methoxycamptothecin. Phytochemistry 71(1):117–122

    Article  CAS  PubMed  Google Scholar 

  • Shweta S, Bindu JH, Raghu J, Suma HK, Manjunatha BL, Kumara PM, Ravikanth G, Nataraja KN, Ganeshaiah KN, Uma Shaanker R (2013) Isolation of endophytic bacteria producing the anti-cancer alkaloid camptothecine from Miquelia dentata Bedd (Icacinaceae). Phytomedicine 20(10):913–917

    Article  CAS  PubMed  Google Scholar 

  • Sirikantaramas S, Asano T, Sudo H, Yamazaki M, Saito K (2007) Camptothecin: therapeutic potential and biotechnology. Curr Pharm Biotechno 8:196–202

    Article  CAS  Google Scholar 

  • Song SH, Byun SY (1998) Elicitation of camptothecin production in cell cultures of Camptotheca acuminata. Biotechnol Bioprocess Eng 3:91–95

    Article  Google Scholar 

  • Stierle A, Strobel G, Stierle D (1993) Taxol and taxane production by Taxomyces andreanae, an endophytic fungus of Pacific yew. Science 260(5105):214–216

  • Sudo H, Yamakawa T, Yamazaki M, Aimi N, Saito K (2002) Bioreactor production of camptothecin by hairy root cultures of Ophiorrhiza pumila. Biotechnol Lett 24:359–363

    Article  CAS  Google Scholar 

  • Sun Y, Luo H, Li Y, Sun C, Song J, Niu Y, Zhu Y, Dong L, Lv A, Tramontano E, Chen S (2011) Pyrosequencing of the Camptotheca acuminata transcriptome reveals putative genes involved in camptothecin biosynthesis and transport. BMC Genomics 12:533

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tafur S, Nelson JD, De Long DC, Svoboda GH (1976) Antiviral components of Ophiorrhiza mungos. Isolation of camptothecin and 10-methoxycamptothecin. Lloydia 39:261–262

    CAS  PubMed  Google Scholar 

  • Valletta A, Trainotti L, Santamaria AR, Pasqua G (2010) Cell-specific expression of tryptophan decarboxylase and 10-hydroxygeraniol oxidoreductase, key genes involved in camptothecin biosynthesis in Camptotheca acuminata Decne (Nyssaceae). BMC Plant Biol 10:69

    Article  PubMed Central  PubMed  Google Scholar 

  • van der Fits L, Memelink J (2000) ORCA3, a jasmonateresponsive transcriptional regulator of plant primary and secondary metabolism. Science 289:295–297

    Article  PubMed  Google Scholar 

  • van Hengel AJ, Harkes MP, Wichers HJ, Hesselink PGM, Buitelaar RM (1992) Characterization of callus formation and camptothecin production by cell lines of Camptotheca acuminata. Plant Cell Tiss Org 28:11–18

    Article  Google Scholar 

  • Wall ME, Wahl MC, Cook CE, Palmer KH, McPhail AT, Sim GA (1966) Plant antitumor agents I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Carnptotheca acurninata. J Amer Chem Soc 88:3888–3890

    Article  CAS  Google Scholar 

  • Wang JW, Wu JY (2013) Effective elicitors and process strategies for enhancement of secondary metabolite production in hairy root cultures. Adv Biochem Eng Biotechnol 134:55–89

    CAS  PubMed  Google Scholar 

  • Wang JW, Wu JY (2010) Tanshinone biosynthesis in Salvia miltiorrhiza and production in plant tissue cultures. Appl Microbiol Biotechnol 88:437–449

  • Wang Q, Pi Y, Hou R, Jiang K, Huang Z, Hsieh MS, Sun X, Tang K (2008a) Molecular cloning and characterization of 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate reductase (CaHDR) from Camptotheca acuminata and its functional identification in Escherichia coli. BMB Rep 41(2):112–118

    Article  CAS  PubMed  Google Scholar 

  • Wang W, Lu Y, Li L, Wang J, Kai GY (2008b) Induction of Hairy Roots from Camptotheca acuminata and the Content of Camptothecin. Acta Bot Boreal Occident Sinica 28(12):2416–2422

    CAS  Google Scholar 

  • Yamamoto H, Katano N, Ooi A, Inoue K (2000) Secologanin synthase which catalyzes the oxidative cleavage of loganin into secologanin is a cytochrome P450. Phytochemistry 53:7–12

    Article  CAS  PubMed  Google Scholar 

  • Yamazaki Y, Sudo H, Yamazaki M, Aimi N, Saito K (2003) Camptothecin biosynthetic genes in hairy roots of Ophiorrhiza pumila: cloning, characterization and differential expression in tissues and by stress compounds. Plant Cell Physiol 44(4):395–403

    Article  CAS  PubMed  Google Scholar 

  • Yamazaki Y, Kitajima M, Arita M, Takayama H, Sudo H, Yamazaki M, Yasuyo Aimi N, Saito K (2004) Biosynthesis of camptothecin. In silico and in vivo tracer study from [1−13C] glucose. Plant Physiol 134:161–170

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yamazaki M, Asano T, Yamazaki Y, Sirikantaramas S, Sudo H, Saito K (2010) Biosynthetic system of camptothecin: an anticancer plant product. Pure Appl Chem 82(1):213–218

    Article  CAS  Google Scholar 

  • Yao HY, Gong YF, Zuo KJ, Ling H, Qiu ChX, Fi Zhang, Wang YC, Pi Y, Liu X, Sun XF, Tang KX (2008) Molecular cloning, expression profiling and functional analysis of a DXR gene encoding 1-deoxy-D-xylulose 5-phosphate reductoisomerase from Camptotheca acuminata. Plant Physiol 165:203–213

    Article  CAS  Google Scholar 

  • Ya-ut P, Chareonsap P, Sukrong S (2011) Micropropagation and hairy root culture of Ophiorrhiza alata Craib for camptothecin production. Biotechnol Lett 33:2519–2526

    Article  CAS  PubMed  Google Scholar 

  • Zabala MA, Angarita M, Restrepo JM, Caicedo LA, Perea M (2010) Elicitation with methyl-jasmonate stimulates peruvoside production in cell suspension cultures of Thevetia peruviana. In Vitro Cell Dev Biol Plant 46:233–238

  • Zhang DY, Zhao XQ, Yu F, Bai FW, An LJ (2002) Callus induction of Camptotheca acumianta and camptothecin production. J Northeast Norm Univ 34(1):45–48

    CAS  Google Scholar 

  • Zhang J, Yu Y, Liu D, Liu ZJ (2007) Extraction and composition of three naturally occurring anti-cancer alkaloids in Camptotheca acuminata seed and leaf extracts. Phytomedicine 14:50–56

    Article  PubMed  Google Scholar 

  • Zhang L, Yan X, Wang J, Li S, Liao P, Kai GY (2011) Molecular cloning and expression analysis of a new putative gene encoding 3-hydroxy-3-methylglutaryl-CoA synthase from Salvia miltiorrhiza. Acta Physiol Plant 33:953–961

    Article  CAS  Google Scholar 

  • Zhao J, Davis LC, Verpoorte R (2005) Elicitor signal transduction leading to production of plant secondary metabolites. Biotechnol Adv 23:283–333

Download references

Acknowledgments

This work was supported by National Natural Science Fund (31201261, 31270007, 30900110), Fok Ying-Tong Education Foundation for Young Teachers in the Higher Education Institutions of China (131041), New Century Talent Project (NECT-13-0902), Shanghai Talent Development Fund, Shanghai Education Committee Fund (13ZZ104, 09ZZ138, J50401), Key Science and Technology Project of Yantze River Delta (10140702018) and Shanghai Young Teacher Training Project of Shanghai Education Committee Fund.

Author information

Authors and Affiliations

  1. Laboratory of Plant Biotechnology, Development Center of Plant Germplasm Resources, College of Life and Environment Sciences, Shanghai Normal University, Shanghai, 200234, China

    Guoyin Kai, Chao Wu, Liyuan Gen, Liqiang Zhang & Lijie Cui

  2. Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Xiaoling Ni

Authors
  1. Guoyin Kai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chao Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liyuan Gen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Liqiang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lijie Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaoling Ni
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guoyin Kai.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kai, G., Wu, C., Gen, L. et al. Biosynthesis and biotechnological production of anti-cancer drug Camptothecin. Phytochem Rev 14, 525–539 (2015). https://doi.org/10.1007/s11101-015-9405-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11101-015-9405-5

Keywords

Search

Navigation