Abstract
Camptothecin (CPT), a monoterpene indole alkaloid (MIA), is the starting material for the synthesis of topotecan and irinotecan which are well known and clinically plant approved antitumor drugs. Here, we investigated the latest progress in the biosynthesis of MIA in Ophiorrhiza and identification of enzymes/genes implicated in CPT biosynthetic pathway. Secologanin and tryptamine are involved in the biosynthesis of MIA and quinoline. Due to lack of knowledge of its enzymes/genes involved, the biosynthesis of CPT has not been well established. Biotechnology plays an important role in the manufacture of pharmaceutical metabolites to maintain industrial production and diminish over-exploitation of natural sources. Instead, new technologies that can be used to solve problems and to achieve overproduction of therapeutic secondary metabolites must be discovered economically viable approaches to the production of CPT. To this viewpoint, plant cell, tissue and organ cultures, cell suspension cultures, precursor feeding, hairy root cultures, bioreactors culture of suspensions/hairy root cultures, and metabolic engineering are reviewed as a cost-effective and alternative for CPT production. The present chapter summarizes the latest procedures/approaches for the enhancement of CPT in Ophiorrhiza using plant cell and tissue culture.
Abbreviations
- 2,4-D :
-
2,4-Dichlorophenoxyacetic acid
- BA :
-
6-Benzyladenine
- CPT:
-
Camptothecin
- DW:
-
Dry weight
- HRCs:
-
Hairy root cultures
- IPP:
-
Isopentenyl diphosphate
- Kin :
-
Kinetin
- MEP:
-
Methylerythritol 4-phosphate pathway
- MIA:
-
Monoterpene indole alkaloid
- MS:
-
Murashige and Skoog medium
- MVA:
-
Mevalonate pathway
- NAA:
-
Naphthalene-1-acetic acid
References
Rather GA, Sharma A, Pandith SA, Kaul V, Nandi U, Misra P, Lattoo SK (2018) De novo transcriptome analyses reveal putative pathway genes involved in biosynthesis and regulation of camptothecin in Nothapodytes nimmoniana (Graham) Mabb. Plant Mol Biol 96(1–2):197–215
Gonçalves S, Romano A (2018) Biotechnological approaches for the propagation of anticancer plants and the production of vital compounds. In: Akhtar MS, Swamy MK (eds) Anticancer plants: natural products and biotechnological implements, vol 2. Springer, Singapore
British Broadcasting Corporation (BBC) research. Plant-derived drugs: global markets (2017) https://www.bccresearch.com/market-research/biotechnology/botanical-and-plant-derived-drugs-global-markets-bio022h.html. Accessed 2018-02-08
Pizzolato JF, Saltz LB (2003) The camptothecins. Lancet 361:2235–2242
Lorence A, Nessler CL (2004) Camptothecin, over four decades of surprising findings. Phytochemistry 65:2735–2749
Patwardhan A (2006) Domestication of Nothapodytes nimmoniana (grah.) Mabb. An endangered medicinal tree from Western Ghats of India. The Rufford Small Grants Foundation, UK, pp 7–15
López-Meyer M, Nessler C, McKnight T (1994) Sites of accumulation of the antitumor alkaloid camptothecin in Camptotheca acuminata. Planta Med 60:558–560
Qu Y, Chu B, Wei X, Lei M, Hu D, Zha R, Zhong L, Wang M, Wang F, Qian Z (2019) Redox/pH dual-stimuli responsive camptothecin prodrug nanogels for “on demand” drug delivery. J Control Release 296:93–106
Wetterauer B, Wildi E, Wink M (2018) Production of the anticancer compound camptothecin in root and hairy root cultures of Ophiorrhiza mungos. In: Kumar N (ed) Biotechnological approaches for medicinal and aromatic plants. Springer, Singapore
Kulkarni A, Patwardhan A, Lele U, Malpathak N (2010) Production of camptothecin in cultures of Chonemorpha grandiflora. Pharm Res 2:296
Gunasekera SP, Badawi MM, Cordell GA, Farnsworth NR, Chitnis M (1979) Plant anticancer agents X. isolation of camptothecin and 9-methoxycamptothecin from Ervatamia heyneaya. J Nat Prod 42:475–477
Arisawa M, Gunasekera S, Cordell G, Farnsworth N (1981) Plant anticancer agents XXI. Constituents of Merrilliodendron megacarpum. Planta Med 43:404–407
Zhou BN, Hoch JM, Johnson RK, Mattern MR, Eng WK, Ma J, Hecht SM, Newman DJ, Kingston DG (2000) Use of COMPARE analysis to discover new natural product drugs: isolation of camptothecin and 9-methoxycamptothecin from anew source. J Nat Prod 63:1273–1276
Dai JR, Halloch YF, Cardellina JH II, Boyd MR (1999) 20-O-β-Glucopyranosyl camptothecin from Mostuea brunonis: a potential camptothecin pro-drug with improved solubility. J Nat Prod 62:1427–1429
Tafur S, Nelson JD, DeLong DC, Svoboda GH (1976) Antiviral components of Ophiorrhiza mungos. Isolation of camptothecin and 10-methoxycamptothecin. Lloydia 39:261–262
Arbain D, Putra DP, Sargent MV (1993) The alkaloids of Ophiorrhiza filistipula. Aust J Chem 46:977–985
Hussain M, Sarfaraj FS, Ansari S, Rahman M, Akhlaquer AIZ, Saeed M (2012) Current approaches toward production of secondary plant metabolites. J Pharm Bioallied Sci 4:10–20
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
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
Yamazaki M, Asano T, Saito K (2013) Camptothecin Production and Biosynthesis in Plant Cell Cultures. In: Gang D (eds) 50 Years of Phytochemistry Research. Recent Advances in Phytochemistry, vol 43. Springer, Cham
The Plant List (2019) http://www.theplantlist.org/tpl1.1/search?q=ophiorrhiza Accessed 3 May 2019
Deb DB, Mondal DC (2001) Taxonomic revision of the genus Ophiorrhiza L. (Rubiaceae) in Indian subcontinent. Bull Bot Surv Ind 39:1–148
Rajan R, Varghese SC, Kurup R, Gopalakrishnan R, Venkataraman R, Satheeshkumar K, Baby S (2013) Search for Camptothecin-yielding Ophiorrhiza species from southern Western Ghats in India: a HPTLC-densitometry study. Ind Crop Prod 43:472–476
Joseph G, Joseph JP (2009) Rediscovery of Ophiorrhiza caudata (Rubiaceae) from the Western Ghats of Kerala. Rheedea 19:45–46
Aimi N, Nishimura M, Miwa A, Hoshino H, Sakai S, Haginiwa J (1989) Structure of ophiorines A and B; novel type glucoindol alkaloids from Ophiorrhiza spp. Tetrahedron Lett 30:4991–4994
Roja G (2006) Comparative studies on the camptothecin content from Nothapodytes foetida and Ophiorrhiza species. Nat Prod Res 20:85–88
Pornwilai Y, Piyarat C, Suchada S (2011) Micropropagation and hairy root culture of Ophiorrhiza alata Craib for camptothecin production. Biotechnol Lett 33:2519–2526
Kitajima M, Fujii N, Yoshino F, Sudo H, Saito K, Aimi N, Takayama H (2005) Camptothecins and two new mono terpene glucosides from Ophiorrhiza liukiuensis. Chem Pharm Bull 53:1355–1358
Roja G (2008) Micropropagation and production of camptothecin from in vitro plants of Ophiorrhiza rugosa var. decumbens. Nat Prod Res 22:1017–1023
Gharpure G, Chavan B, Lele U, Hastak A, Bhave A, Malpure N, Vasudeva R, Patwardhan A (2010) Camptothecin accumulation in Ophiorrhiza rugosa var prostrata from Northern Western Ghats. Curr Sci 98:302–304
Kai GY, Dai LM, Mei XY, Zheng JG, Wang W, Lu Y et al (2008) In vitro plant regeneration from leaf explants of Ophiorrhiza japonica. Biol Plant 52(3):557–560
Pu X, Zhang CR, Zhu L, Li QL, Huang QM, Zhang L, Luo YG (2019) Possible clues for camptothecin biosynthesis from the metabolites in camptothecin-producing plants. Fitoterapia 134:113–128
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
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
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
Mahmoud SS, Croteau RB (2001) Metabolic engineering of essential oil yield and composition in mint by altering expression of deoxy xylulose phosphate reductoisomerase and menthofuran synthase. Proc Natl Acad Sci USA 98:8915–8920
Shi M, Luo XQ, Ju GH, Yu XH, Hao XL, Huang Q, Xiao JB, Cui LJ, Kai GY (2014) Increased accumulation of the cardiocerebrovascular 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 Genomics 14(3):603–615
Yao HY, Gong YF, Zuo KJ, Ling H, Qiu CX, Zhang F, 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
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 and functional expression in Escherichia coli. DNA Seq 19(2):98–105
Yamazaki Y, Sudo H, Yamazaki M et al (2003) Camptothecin biosynthetic genes in hairy roots of Ophiorrhiza pumila: cloning, characterization and differential expression in tissues and by stress compounds. Plant Cell Physiol 44:395–403
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
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
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 U S A 86:2582–2586
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
Lu Y, Wang H, Wang W, Qian Z, Li L, Wang J, Zhou G, Kai G (2009) Molecular characterization and expression analysis of a new cDNA encoding strictosidine synthase from Ophiorrhiza japonica. Mol Biol Rep 36(7):1845–1852
Pasquali G, Goddijn OJ, de Waal A, Verpoorte R, Schilperoort RA, Hoge JHC, Memelink J (1992) Coordinated regulation of two indole alkaloid biosynthetic genes from Catharanthus roseus by auxin andelicitors. Plant Mol Biol 18(6):1121–1131
Menke FL, Champion A, Kijne JW, Memelink J (1999) A novel jasmonate- and elicitor-responsive element in the periwinkle secondary metabolite biosynthetic gene STR interacts with a Jasmonate- and elicitor-inducible AP2-domain transcription factor, ORCA2. EMBO J 18(16):4455–4463
Martin T, Watase I, Sudo H, Kitajima M, Takayama H, Aimi N, Yamasaki M, Saito K (2004) Camptothecin production by in vitro cultures of Ophiorrhiza liukiuensis and O. kuroiwai. Plant Biotechnol 21:275–281
Aimi N, Nishimura M, Miwa A, Hoshino H, Sakai H, Haginiwa J (1989) Pumiloside and deoxypumiloside; plausible intermediates of camptothecin biosynthesis. Tetrahedron Lett 30:4991–4994
Kitajima M, Fujii N, Yoshino F, Sudo H, Saito K, Aimi N, Takayama H (2005) Camptothecins and two new monoterpene glucosides from Ophiorrhiza liukiuensis. Chem Pharm Bull 53:1355–1358
Hussain MS, Fareed S, Ansari S, Rahman MA, Ahmad IZ, Saeed M (2012) Current approaches toward production of secondary plant metabolites. J Pharm Bioallied Sci 4:10–20
Deepthi S, Satheeshkumar K (2016) Enhanced camptothecin production induced by elicitors in the cell suspension cultures of Ophiorrhiza mungos Linn. Plant Cell Tissue Organ Cult 124:483–493
Wink M, Alfermann AW, Franke R, Wetterauer B, Distl M, Windhovel J, Krohn O, Fuss E, Garden H, Mohagheghzadeh A, Wildi E, Ripplinger P (2005) Sustainable bioproduction of phytochemicals by plant in vitro cultures: anticancer agents. Plant Genet Resour Char Util 3:90–100
Deepthi S, Satheeshkumar K (2017) Cell line selection combined with jasmonic acid elicitation enhance camptothecin production in cell suspension cultures of Ophiorrhiza mungos L. Appl Microbiol Biotechnol 101(2):545–558
Krishnan JJ, Gangaprasad A, Satheeshkumar K (2018) Biosynthesis of camptothecin from callus and cell suspension cultures of Ophiorrhiza mungos L. var. angustifolia (Thw.) Hook. f. Proc Natl Acad Sci India Sect B Biol Sci 89(3):893–902. https://doi.org/10.1007/s40011-018-1003-z
Jisha KG (2006) A study on the production of camptothecin from Ophiorrhiza mungos and Nothapodytes foelida using cell and tissue culture. Thesis submitted to Mahatma Gandhi University through Amala Cancer Research Centre, Thrissur (in partial fulfillment of the requirements for award of Doctor of Philosophy)
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
Sharma P, Padh H, Shrivastava N (2013) Hairy root cultures: a suitable biological system for studying secondary metabolic pathways in plants. Eng Life Sci 13:62–75
Ya-ut P, Chareonsap P, Sukrong S (2011) Micropropagation and hairy root culture of Ophiorrhiza alata Craib for camptothecin production. Biotechnol Lett 33(12):2519–2526
Panjikar S, Stoeckigt J, O’Connor S, Warzecha H (2012) The impact of structural biology on alkaloid biosynthesis research. Nat Prod Rep 29:1176–1200
Miettinen K, Dong L, Navrot N, Schneider T, Burlat V, Pollier J, Woittiez L, van der Krol S, Lugan R, Ilc T, Verpoorte R, Oksman-Caldentey KM, Martinoia E, Bouwmeester H, Goossens A, Memelink J, Werck-Reichhart D (2014) The seco-iridoid pathway from Catharanthus roseus. Nat Commun 5:3606
Padhan JK, Kumar V, Sood H, Singh TR, Chauhan RS (2015) Contents of therapeutic metabolites in Swertia chirayita correlate with the expression profiles of multiple genes in corresponding biosynthesis pathways. Phytochemistry 116:38–47
Namdeo A, Priya T, Bhosale B (2012) Micropropagation and production of camptothecin form in vitro plants of Ophiorrhiza mungos. Asia Pac J Trop Biomed 2(2):S662–S666
Krishnan JJ, Gangaprasad A, Satheeshkumar K (2018) Adventitious shoot regeneration from in vitro leaf explants of Ophiorrhiza mungos L. var. angustifolia (Thw.) Hook. F. Int J Agric Environ Biotech 11(1):65–70
Martin KP, Zhang C-L, Hembrom ME, Slater A, Madassery J (2008) Adventitious root induction in Ophiorrhiza prostrata: a tool for the production of camptothecin (an anticancer drug) and rapid propagation. Plant Biotechnol Rep 2(2):163–169
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(5):359–363
Krishnan JJ, Gangaprasad A, Satheeshkumar K (2018) In vitro mass multiplication and estimation of camptothecin (CPT) in Ophiorrhiza mungos L. var. angustifolia (Thw.) Hook. f. Ind Crop Prod 119:64–72
Deepthi S, Satheeshkumar K (2017) Effects of major nutrients, growth regulators and inoculum size on enhanced growth and camptothecin production in adventitious root cultures of Ophiorrhiza mungos L. Biochem Eng J 117:198–209
Krishnakumar G, Satheeshkumar K, Krishnan PN (2018) Tissue culture studies and estimation of camptothecin from Ophiorrhiza prostrata D. Don. Ind J Plant Physiol 23(3):582–592
Vineesh VR, Jelly CL, Fijesh PV, Jaimsha VK, Padikkala J (2007) Effect of N6-benzyl amino purine and naphthalene acetic acid on camptothecin production through in vitro propagation of Ophiorrhiza rugosa Wall. var. decumbens (Gardn. ex Thw.) Deb & Mondal. Nat Prod Radiance 6(5):405–409
Rani VKJ, Fijesh PV, Padikkala J (2010) Micropropagation of Ophiorrhiza eriantha Wight. through leaf explant cultures. Plant Tissue Cult Biotech 20(1):13–20
Watase I, Sudo H, Yamazaki M, Saito K (2004) Regeneration of transformed Ophiorrhiza pumila plants producing camptothecin. Plant Biotechnol 21(5):337–342
Kamble S, Gopalakrishnan R, Eapen S (2011) Production of camptothecin by hairy roots and regenerated transformed shoots of Ophiorrhiza rugosa var. decumbens. Nat Prod Res 25(18):1762–1765
Sibi CV, Renjith R, Roja G, Ravichandran P, Satheeshkumar K (2016) A novel and efficient method for the enhanced production of multiple shoots and camptothecin from Ophiorrhiza trichocarpos Blume through subculture passages in media of alternating strength. Eur J Biotechnol Biosci 4(12):12–16
Asano T, Watase I, Sudo H, Kitajima M, Takayama H, Aimi N, Yamazaki M, Saito K (2004) Camptothecin production by in vitro cultures O. liukiuensis and O. kuroiwai. Plant Biotechnol 21(4):275–281
Acknowledgments
The authors are thankful to the Director, CSIR-CIMAP, Lucknow, India, for providing necessary facilities for carrying out the research work. The first author also gratefully thanks to National Post-Doctoral Fellowship (Sanction Order No: PDF/2017/000368), Science and Engineering Research Board, Department of Science and Technology, Government of India for the financial support to carry out this research.
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Mahendran, G., Rahman, L.u. (2020). Biosynthesis and Biotechnological Production of Anticancer Drug Camptothecin in Genus Ophiorrhiza. In: Ramawat, K., Ekiert, H., Goyal, S. (eds) Plant Cell and Tissue Differentiation and Secondary Metabolites. Reference Series in Phytochemistry. Springer, Cham. https://doi.org/10.1007/978-3-030-11253-0_32-1
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