Fungal Endophytes from Anticancer Plants as Producers of the Antitumor Agent L-Asparaginase: A Look at Diversity, Ubiquity, and Enzyme Production

  • Yiing Yng Chow
  • Wei Shang Tan
  • Adeline Su Yien TingEmail author


Endophytes are microorganisms inhabiting plants without causing any visible symptoms. In recent years, endophytes from medicinal or anticancer plants have demonstrated the ability to produce bioactive compounds similar to anticancer compounds derived from their host plant, i.e., taxol from Taxomyces andreanae found in the Pacific yew tree. In this study, we explored endophytes from several common medicinal plants for their potential to produce L-asparaginase, an anticancer agent that deprives tumor cells from L-asparagine. The plants selected have been documented for their ethnobotanical anticancer properties, which include Cymbopogon citratus, Murraya koenigii, Oldenlandia diffusa, Pereskia bleo, and Andrographis paniculata. The fungal endophytes were isolated and identified and their L-asparaginase production was determined. Results revealed that anticancer plants do harbor a diverse group of fungal endophytes, and their distribution and relative abundance vary according to plant parts (roots, stem, leaves). The number of endophytes isolated is highest from A. paniculata (50 isolates), followed by P. bleo (40 isolates), O. diffusa (25 isolates), C. citratus (14 isolates), and M. koenigii (10 isolates). Most of the fungal endophytes are species of Colletotrichum, Fusarium, Penicillium, Phoma, and Aspergillus. Comparison of the species diversity in each plant part showed that roots typically harbor the most number of endophytes isolated, followed by leaf or stem tissues. Nevertheless, the number of isolates with L-asparaginase production differs among plants. A. paniculata has the most number of endophytes with L-asparaginase activities (39 of the 50 isolates), compared to P. bleo, O. diffusa, C. citratus, and M. koenigii with 15, 7, 2, and 1 positive isolate(s), respectively. Their L-asparaginase activities quantified were between 0.009 and 0.0246 M−1 mL−1 min−1 of mean L-asparaginase activity, with higher levels derived from endophytes from O. diffusa. Our study has shown that endophytes from anticancer plants have the potential as producers of L-asparaginase. They can be developed for upscale production under optimized conditions, to produce sufficient L-asparaginase for cancer treatment.


L-Asparaginase Anticancer plants Endophytes 



The authors extend their gratitude to Monash University Malaysia for the opportunity and the funding that enable the authors to continue with the pursuit of research in endophytes and enable the publication of key results by the authors discussed here.


  1. Akinsanya MA, Ting ASY, Goh JK, Lim SP (2016) Biodiversity, enzymatic and antimicrobial activities of bacterial endophytes in selected local medicinal plants. J Biomed Pharm Res 5:76–88Google Scholar
  2. Aly AH, Debbab A, Proksch P (2013) Fungal endophytes-secret producers of bioactive plant metabolites. Pharmazie 68:499–505PubMedPubMedCentralGoogle Scholar
  3. Arehart C, Rouleau B (2013) Isolation of endophytic bacteria from roots of lemongrass (Cymbopogon citratus). Eur J Agric Sci 10:2668–3547Google Scholar
  4. Aribart T (2011) Inventor; Pegylated L-asparaginase, Patents No. EP 2451486 A1Google Scholar
  5. Asaolu MF, Oyeyemi OA, Olanlokun JO (2009) Chemical compositions, phytochemical constituents and in vitro biological activity of various extracts of Cymbopogon citratus. Pak J Nutr 8:1920–1922CrossRefGoogle Scholar
  6. Audipudi AV, Supriya GNR, Pallavi R, Mani G (2014) Characterization of L-asparaginase production by endophytic fungi isolated from ripened fruit of Capsicum frutescence. Int J Pharma Dev Technol 4:52–57Google Scholar
  7. Bakker PAHM, Pierterse CMJ, Van Loon LC (2007) Induced systemic resistance by fluorescens Pseudomonas spp. Phytopathology 97:239–243PubMedCrossRefGoogle Scholar
  8. Balap A, Lohidasan S, Sinnathambi A, Mahadik K (2017) Herb-drug interaction of Andrographis paniculata (Nees) extract and andrographolide on pharmacokinetic and pharmacodynamics of naproxen in rats. J Ethnopharmacol 195:214–221PubMedCrossRefGoogle Scholar
  9. Baskar G, Rajasekar V, Renganathan S (2011) Modeling and optimization of L-asparaginase production by Enterobacter aerogenes using artificial neural network linked genetic algorithm. Int J Chem Eng Appl 2:98–100Google Scholar
  10. Behera PR, Nayak P, Baric DP, Rautray TR, Thirunavoukkarasu M, Chand PK (2010) ED-XRF spectrometric analysis of comparative elemental composition of in vivo and in vitro roots of Andrographis paniculatata (Burm. f.) Wall. ex Nees-a multi-medicinal herb. Appl Radiat Isot 68:2229–2236PubMedCrossRefGoogle Scholar
  11. Biot-Pelletier D, Martin VJ (2014) Evolutionary engineering by genome shuffling. Appl Microbiol Biotechnol 98:3877–3887PubMedCrossRefGoogle Scholar
  12. Cachumba JJM, Antunes FAF, Peres GFD, Brumano LP, Santos JCD, Silva SSD (2016) Current applications and different approaches for microbial L-asparaginase production. Braz J Microbiol 47:77–85PubMedPubMedCentralCrossRefGoogle Scholar
  13. Channabasava, Govindappa M (2014) First report of anticancer agent, lapachol producing endophyte, Aspergillus niger of Tabebuia argentea and its in vitro cytotoxicity assays. Bangladesh J Pharmacol 9:129–139CrossRefGoogle Scholar
  14. Chithra S, Jasmin B, Sachidanandan P, Jyothis M, Radhakrishnan EK (2014) Piperine production by endophytic fungus Colletotrichum gloeosporioides isolated from Piper nigrum. Phytomedicine 21:534–540PubMedCrossRefGoogle Scholar
  15. Chow YY, Ting ASY (2015) Endophytic L-asparaginase-producing fungi from plants associated with anticancer properties. J Adv Res 6:869–876PubMedCrossRefGoogle Scholar
  16. Cragg GM, Newman DJ (2003) Plants as a source of anti-cancer and anti-HIV agents. Ann Appl Biol 143:127–133CrossRefGoogle Scholar
  17. Deshmukh SK, Kolet MJ, Verekar SA (2010) Distribution of endophytic fungi in lemongrass (Cymbopogon citratus (DC.) Stapf.) J Cell Tissue Res 10:2263–2267Google Scholar
  18. Devi RC, Sim SM, Ismail R (2011) Spasmolytic effect of citral and extracts of Cymbopogon citratus on isolated rabbit ileum. J Smooth Muscle Res 47:143–156PubMedCrossRefGoogle Scholar
  19. Dias FFG, de Castro RJS, Ohara A, Nishide TG, Bagagli MP, Sato HH (2015) Simplex centroid mixture design to improve L-asparaginase production in solid-state fermentation using agroindustrial wastes. Biocatal Agric Biotechnol 4:528–534Google Scholar
  20. El-Naggar NEA (2015) Extracellular production of the oncolytic enzyme, L-asparaginase, by newly isolated Streptomyces sp. strain NEAE-95 as potential microbial cell factories: optimization of culture conditions using response surface methodology. Curr Pharmaceut Biotechnol 16:162–178CrossRefGoogle Scholar
  21. El-Naggar NEA, El-Ewasy SM, El-Shweihy NM (2014) Microbial l-asparaginase as a potential therapeutic agent for the treatment of acute lymphoblastic leukemia: the pros and cons. Int J Pharm 10:182–199CrossRefGoogle Scholar
  22. El-said AHM, Shebany YM, Hussein MA, El-Dawy EGA (2016) Antimicrobial and L-asparaginase activities of endophytic fungi isolated from Datura innoxia and Hyoscyamus muticus medicinal plants. Eur J Biol Res 6:135–144Google Scholar
  23. Er HM, Cheng EH, Radhakrishnan AK (2007) Anti-proliferative and mutagenic activities of aqueous and methanol extracts of leaves from Pereskia bleo (Kunth) DC (Cactaceae). J Ethnopharmacol 113:448–456PubMedCrossRefGoogle Scholar
  24. Erva RR, Goswami AN, Suman P, Vedanabhatla R, Rajulapati SB (2017) Optimization of L-asparaginase production from novel Enterobacter sp., by submerged fermentation using response surface methodology. Prep Biochem Biotechnol 47:219–228PubMedCrossRefGoogle Scholar
  25. Farag AM, Hassan SW, Beltagy EA, El-Shenaway MA (2015) Optimization of production of anti-tumor L-asparaginase by free and immobilized marine Aspergillus terreus. Egypt J Aquat Res 41:295–302CrossRefGoogle Scholar
  26. Feng T, Zhao Y (2017) Clinical anticancer drugs for cancer treatment. In: Feng T, Zhao Y (eds) Nanomaterial-based drug delivery carriers for cancer therapy. Springer briefs in applied sciences and technology. Springer, Singapore, pp 7–13CrossRefGoogle Scholar
  27. Fernandes HS, Teixeira CSS, Fernandes PA, Ramos MJ, Cerqueira NMFSA (2017) Amino acid deprivation using enzymes as a targeted therapy for cancer and viral infections. Exp Opin Ther Pat 27:283–297CrossRefGoogle Scholar
  28. Gajalakshmi S, Iswarya V, Ashwini R, Bhuvaneshwari M, Mythili S, Sathiavelu A (2012) Secondary metabolite production by endophytic fungi isolated from Andrographis paniculata. Int J Biomed Sci Technol 5:12–17Google Scholar
  29. Gangadevi V, Muthumary J (2008) Isolation of Colletotrichum gloeosporioides, a novel endophytic taxol-producing fungus from the leaves of a medicinal plant, Justicia gendarussa. Mycol Balc 5:1–4Google Scholar
  30. Greenwell M, Rahman PKSM (2015) Medicinal plants: their use in anticancer treatment. Int J Pharm Sci Res 6(10):4103–4112Google Scholar
  31. Grothaus PG, Cragg GM, Newman DJ (2010) Plant natural products in anticancer drug discovery. Curr Org Chem 14:1781–1791CrossRefGoogle Scholar
  32. Guo B, Wang Y, Sun X, Tang K (2008) Bioactive natural products from endophytes: a review. Appl Biochem Microbiol 44:136CrossRefGoogle Scholar
  33. Gupta S, Zhang D, Yi J, Shao J (2004) Anticancer activities of Oldenlandia diffusa. J Herb Pharmacother 4:21–33CrossRefPubMedGoogle Scholar
  34. Harper JK, Arif AM, Ford EJ (2003) Pestacin: a 1, 3-dihydro isobenzofuran from Pestalotiopsis microspora possessing antioxidant and antimycotic activities. Tetrahedron 59:2471–2476CrossRefGoogle Scholar
  35. Hendriksen HV, Kornbrust BA, Østergaard PR, Stringer MA (2009) Evaluating the potential for enzymatic acrylamide mitigation in a range of food products using an asparaginase from Aspergillus oryzae. J Agric Food Chem 57:4168–4176PubMedCrossRefGoogle Scholar
  36. Hermanto A, Ting ASY (2016) Comparative effect of L-asparagine and sodium nitrate in inducing L-asparaginase production by endophytic Fusarium sp. Acta Biol Szeged 60:145–150Google Scholar
  37. Hu X, Li W, Yuan M, Li CF, Liu SX, Jiang CJ, YC W, Cai K, Liu Y (2016) Homoharringtonine production by endophytic fungus isolated from Cephalotaxus hainanensis Li. World J Microbiol Biotechnol 32:110. CrossRefPubMedGoogle Scholar
  38. Huang WY, Cai YZ, Xing J, Corke H, Sun MA (2007) A potential antioxidant resource: endophytic fungi from medicinal plants. Econ Bot 61:14–30CrossRefGoogle Scholar
  39. Hymavathi M, Sathish T, Rao CS, Prakasham RS (2009) Enhancement of L-asparaginase production by isolated Bacillus circulans (MTCC 8574) using response surface methodology. Appl Biochem Biotechnol 159:191–198PubMedCrossRefGoogle Scholar
  40. Islam MS, Akhtar MM, Rahman MM, Rahman MA, Sarker KK, Alam MF (2009) Antitumor and phytotoxic activities of leaf methanol extract of Oldenlandia diffusa (wild.) Roxb. Global J Pharmacol 3:99–106Google Scholar
  41. Jalgaonwala RE, Mahajan RT (2014) Production of anticancer enzyme asparaginase from endophytic Eurotium sp. isolated from rhizomes of Curcuma longa. Eur J Exp Biol 4:36–43Google Scholar
  42. Kamble KD, Bidwe PR, Muley VY, Kamble LH, Bhadange DG, Musaddiq M (2012) Characterization of l-asparaginase producing bacteria from water, farm and saline soil. Biosci Discov 3:116–119Google Scholar
  43. Kang SH, Cho HS, Cheong H, Ryu CM, Kim JF, Park SH (2007) Two bacterial endophytes eliciting boot plant growth promotion and plant defense on pepper (Capsicum annum L.) Microbiol Biotechnol J 17:96–103Google Scholar
  44. Kharwar RN, Mishra A, Gond SK, Stierle A, Stierle D (2011) Anticancer compounds derived from fungal endophytes: their importance and future challenges. Nat Prod Rep 28:1208–1228CrossRefPubMedGoogle Scholar
  45. Korejo F, Ali SA, Shafique A, Sultana V, Ara J, Ehteshamui-Haque S (2014) Antifungal and antibacterial activity of endophytic Penicillium species isolated from Salvadora species. Pak J Bot 46:2313–2318Google Scholar
  46. Kotzia GA, Labrou NE (2007) L-Asparaginase from Erwinia chrysanthemi 3937: cloning, expression and 366 characterization. J Biotechnol 127:657–669PubMedCrossRefGoogle Scholar
  47. Kour A, Shawl AS, Rehman S, Sultan P, Qazi PH, Suden P, Khajuria RK, Verma V (2008) Isolation and identification of an endophytic strain of Fusarium oxysporum producing podophyllotoxin from Juniperus recurva. World J Microbiol Biotechnol 24:1115–1121CrossRefGoogle Scholar
  48. Krishnamurthy YL, Hemalatha TV (2008) Isolation of endophytic fungi from some grasses. J Mycol Plant pathol 33(2):305–306Google Scholar
  49. Krishnapura PR, Belur PD (2016) Isolation and screening of endophytes from the rhizomes of some Zingiberaceae plants for L-asparaginase production. Prep Biochem Biotechnol 46:281–287PubMedCrossRefGoogle Scholar
  50. Kumar DS, Sobha K (2012) L-asparaginase from microbes: a comprehensive review. Adv Bioresour 3:137–157Google Scholar
  51. Kumar RA, Sridevi K, Vijaya KN, Nanduri S, Rajagopal S (2004) Anticancer and immunostimulatory compounds from Andrographis paniculata. J Ethnopharmacol 92:291–295PubMedCrossRefGoogle Scholar
  52. Kumar A, Patil D, Rajamohanan PR, Ahmad A (2013) Isolation, purification and characterization of vinblastine and vincristine from endophytic fungus Fusarium oxysporum isolated from Catharanthus roseus. PLoS One 8:e71805. CrossRefPubMedPubMedCentralGoogle Scholar
  53. Kumar R, Sedolkar VK, Triveni AG, Kumar MS, Shivannavar CT, Gaddad SM (2015) Isolation, screening and characterization of L-asparaginase producing fungi from medicinal plants. Int J Pharm Pharm Sci 8:281–283Google Scholar
  54. Kumara MP, Zuehlke S, Priti V, Ramesha BT, Shweta S, Ravikanth G, Vasudeva R, Santhoshkumar TR, Spiteller M, Shaanker UR (2012) Fusarium proliferatum, an endophytic fungus from Dysoxylum binectariferum Hook. f, produces rohitukine, a chromane alkaloid possessing anti-cancer activity. Anton Van Leeuwen 101:323–329CrossRefGoogle Scholar
  55. Kumaran RS, Muthumary J, Hur BK (2008) Production of taxol from Phyllosticta spinarum, an endophytic fungus of Cupressus sp. Eng Life Sci 8:438–446CrossRefGoogle Scholar
  56. Kusari S, Lamshoft M, Spiteller M (2009) Aspergillus fumigates Fresenius an endophytic fungus from Juniperus communis L. Horstmann as a novel source of the anticancer pro-drug deoxypodophyllotoxin. J Appl Microbiol 107:1019–1030PubMedCrossRefGoogle Scholar
  57. Lakshman HC, Murthy NK, Pushpalatha KC, Jambagi R (2010) Biodiversity of endophytic fungi isolated from selected graminaceous hosts of Mercara region in Karnataka. Inter J Plant Protect 3:335–341Google Scholar
  58. Lapmak K, Lumyong S, Thongkuntha S, Wongputtisin P, Sardsud U (2010) L-asparaginase production by Bipolaris sp. BR438 isolated from brown rice in Thailand. Chiang Mai J Sci 37:160–164Google Scholar
  59. Li LZ, Xie TH, Li HJ, Qin C, Zhang GM, Sun MS (2007) Enhancing the thermostability of Escherichia coli L-asparaginase II by substitution with pro in predicted hydrogen-bonded turn structures. Enzyme Microbiol Technol 41:523–527CrossRefGoogle Scholar
  60. Lin ZJ, Lu ZY, Zhu TJ, Fang YC, Gu QQ, Zhu WM (2008) Penicillenols from Penicillium sp. GQ-7, an endophytic fungus associated with Aegiceras corniculatum. Chem Pharm Bull 56:217–221PubMedCrossRefGoogle Scholar
  61. Liu J, Luo J, Ye H, Sun Y, Lu Z, Zeng X (2009) Production, characterization and antioxidant activities in vitro of exopolysaccharides from endophytic bacterium Paenibacillus polymyxa EJS-3. Carbohydr Polym 78:275–281CrossRefGoogle Scholar
  62. Lopes AM, Oliveira-Nascimento LD, Ribeiro A, Tairum CA Jr, Breyer CA, Oliveira MAD, Monteiro G, Souza-Motta CMD, Magalhães PDO, Avendaño JGF, Cavaco-Paulo AM, Mazzola PG, Rangel-Yagui CDO, Sette LD, Converti A, Pessoa A (2017) Therapeutic l-asparaginase: upstream, downstream and beyond. Crit Rev Biotechnol 37:82–99PubMedCrossRefGoogle Scholar
  63. Lu JJ, Dang YY, Huang M, Xu WS, Chen XP, Wang YT (2012) Anticancer properties of terpenoids isolated from Rhozoma cucrumae-A review. J Ethnopharmacol 143(2):406–411Google Scholar
  64. Manasa C, Nalini M (2014) L-asparaginase activity of fungal endophytes from Tabernaemontana heyneana Wall. (Apocynaceae), endemic to the Western Ghats (India). Int Sch Res Notices 2014:925131. CrossRefPubMedPubMedCentralGoogle Scholar
  65. Mans DRA, Jung FA, Schwartsmann G (1994) Anticancer drug discovery and development. J Brazilian Ass Adv Sci 46:70–81Google Scholar
  66. Masetti R, Pession A (2009) First-line treatment of acute lymphoblastic leukemia with pegasparaginase. Biologics 3:359–368PubMedPubMedCentralGoogle Scholar
  67. Masumi S, Mirzaei S, Kalvandi R, Zafari D (2014) Asparaginase and amylase activity of thyme endophytic fungi. J Crop Protect 3:655–662Google Scholar
  68. Mehanni MM, Safwat MSA (2010) Endophytes of medicinal plants. Acta Hort 854:31–39CrossRefGoogle Scholar
  69. Mohanta J, Tayung K, Mohapatra U (2007) Antimicrobial potentials of endophytic fungi inhabiting three ethno-medicinal plants of Similipal biosphere reserve, India. Internet J Microbiol 5:1–7Google Scholar
  70. Moharram AM, Zohri AA, Seddek NH (2016) L-asparaginase production by endophytic fungi isolated from Withania somnifera in Egypt. SS Int J Multidiscip Res 2:30–40Google Scholar
  71. Muthumani P, Venkatraman S, Ramseshu KV, Meera R, Devi P, Kameswari B, Eswarapriya B (2009) Pharmacological studies of anticancer, antiinflammatory activities of Murraya koenigii (Linn) Spreng in experimental animals. J Pharm Sci Res 1:137–141Google Scholar
  72. Nadeem M, Khan S, Akmal M, Ram M, Al-Qurainy F, Abidin MZ (2012) Genetic diversity and podophyllotoxin analysis of Podophyllum hexandrum from Indian central Himalaya. South Asian J Exp Biol 2:51–56Google Scholar
  73. Narang AS, Desai DS (2009) Pharmaceutical perspectives of cancer therapeutics. Springer Science, Business Media, LLC, New YorkGoogle Scholar
  74. Nath A, Pathak J, Joshi SR (2014) Bioactivity assessment of endophytic fungi associated with Centella asiatica and Murraya koenigii. J Appl Biol Biotechnol 2:6–11Google Scholar
  75. Nelson KE, Nelson BJ (2012) Genetic diversity of microbial endophytes and their biotechnical applications. In: Strobels G (ed) Genomics applications for the developing world, advances in microbial ecology. Springer Science, New York, pp 249–262CrossRefGoogle Scholar
  76. Newmann DJ, Cragg GM (2007) Natural products as sources of new drugs over the last 25 years. J Nat Prod 70:461–477CrossRefGoogle Scholar
  77. Oza VP, Trivedi SD, Parmar PP, Subramanian RB (2009) Withania somnifera (Ashwagandha): a novel source of L-asparaginase. J Integr Plant Biol 51:201–206PubMedCrossRefGoogle Scholar
  78. Palem PPC, Kuriakose GC, Jayabaskaran C (2016) An endophytic fungus, Talaromyces radicus, isolated from Catharanthus roseus, produces vincristine and vinblastine which induce apoptotic cell death. PLoS One 11:e0153111. CrossRefPubMedPubMedCentralGoogle Scholar
  79. Pandey PK, Singh S, Yadav RNS, Singh AK, Singh MCK (2014) Fungal endophytes: promising tools for pharmaceutical science. Inter J Pharm Sci Rev Res 25:128–138Google Scholar
  80. Pandi M, Manikandan R, Muthumary J (2010) Anticancer activity of fungal taxol derived from Botryodiplodia theobromae Pat., an endophytic fungus against 7, 12 dimethyl benz(a)anthracene (DMBA)-induced mammary gland carcinogenesis in Sprague dawley rats. Biomed Pharmacother 64:48–53PubMedCrossRefGoogle Scholar
  81. Patidar DK, Yadav N, Nakra V, Sharma P, Bagherwal A (2010) Wound healing activity of Murraya koenigii leaf extract. Pharmacie Globale 4:1–2Google Scholar
  82. Patil MP, Patil RH, Mahjeshwari VL (2012) A novel and sensitive agar plug assay for screening of asparagine-producing endophytic fungi from Aegle marmelos. Acta Biol Szeged 56:175–177Google Scholar
  83. Pieters R, Hunger SP, Boos J, Rizzari C, Silverman L, Baruchel A, Goekbuget N, Schrappe M, Pui CH (2011) L-asparaginase treatment in acute lymphoblastic leukemia: a focus on Erwinia asparaginase. Cancer 15:238–249CrossRefGoogle Scholar
  84. Pu X, XX Q, Chen F, Bao JK, Zhang GL, Luo YG (2013) Camptothecin-producing endophytic fungus Trichoderma atroviride LY357: isolation, identification and fermentation conditions optimization for camptothecin production. Appl Microbiol Biotechnol 97:9365–9375PubMedCrossRefGoogle Scholar
  85. Qin JC, Zhang YM, Gao JM, Bai MS, Yang SX, Laatsch H, Zhang AL (2009) Bioactive metabolites produced by Chaetomium globosum, an endophytic fungus isolated from Ginkgo biloba. Bioorg Med Chem Lett 19:1572–1574PubMedCrossRefGoogle Scholar
  86. Rani SA, Sundaram L, Wasantha PB (2012) Isolation and screening of l-asparaginase producing fungi from soil sand. Inter J Pharm Pharmaceut Sci 4:279–282Google Scholar
  87. Ratych OT, Robison RS, Berk B, Inc SS (1970) Inventors; Synthesis of L-asparaginase. Patents No. US 3511755Google Scholar
  88. Rodriguez JA, Astudillo L, Hirschmann GS (2003) Oleanolic acid promotes healing of acetic acid-induced chronic gastric lesions in rats. Pharmacol Res 48:291–294PubMedCrossRefGoogle Scholar
  89. Runnie I, Salleh MN, Mohamed S, Head RJ, Abeywardena MY (2004) Vasorelaxation induced by common edible tropical plant extracts in isolated rat aorta and mesenteric vascular bed. J Ethnopharmacol 92:311–316PubMedCrossRefGoogle Scholar
  90. Samudio I, Konopleva M (2013) Asparaginase unveils glutamine-addicted AML. Blood 122:3398–3400PubMedCrossRefGoogle Scholar
  91. Sanwal CS, Kumar R, Bhardwaj SD (2016) Integration of Andrographis paniculata as potential medicinal plant in chir pine (Pinus roxburghii Sarg.) plantation of north-western Himalaya. Scientifica 2016:2049532. CrossRefPubMedPubMedCentralGoogle Scholar
  92. Senthilkumar M, Govindasamy V, Annapura K (2007) Role of antibiosis in suppression of charcoal rot disease by soybean endophyte Paenibacillus HKA-15. Curr Microbiol 55:25–29PubMedCrossRefGoogle Scholar
  93. Shah AS, Wakade AS, Juvekar AR (2008) Immunomodulatory activity of methanolic extract of Murraya koenigii (L) Sprengel leaves. Indian J Exp Biol 46:505–509PubMedGoogle Scholar
  94. Sharma PR, Mondhe DM, Muthiah S, Pal HC, Shah AK, Saxena AK, Qazi GN (2008) Anticancer activity of an essential oil from Cymbopogon flexuosus. Chem Biol Interact 79:160–168Google Scholar
  95. Shweta S, Gurumurthy BR, Ravikanth G, Ramanan US, Shivanna MB (2013) Endophytic fungi from Miquelia dentata Bedd., produce the anti-cancer alkaloid, camptothecin. Phytomedicine 20:337–342PubMedPubMedCentralCrossRefGoogle Scholar
  96. Sim KS, Nurestri AMS, Norhanom AW (2010) Phenolic content and antioxidant activity of crude and fractionated extracts of Pereskia bleo (Kunth) DC. (Cactaceae). African J Pharm Pharmacol 4:193–201Google Scholar
  97. Sivapathasekaran C, Mukherjee S, Ray A, Gupta A, Sen R (2010) Artificial neural network modeling and genetic algorithm based medium optimization for the improved production of marine biosurfactant. Bioresour Technol 101:2884–2887PubMedCrossRefGoogle Scholar
  98. Sousa SM, Silva PS, Viccini LF (2010) Cytogenotoxicity of Cymbopogon citratus (DC) Stapf (lemongrass) aqueous extracts in vegetal test systems. An Acad Bras Ciênc 82:305–311PubMedCrossRefGoogle Scholar
  99. Strobel GA, Torzynski R, Bollon A (1997) Acremonium sp.-a leucinostatin a producing endophyte of European Yew (Taxus baccata). Plant Sci 128:97–108CrossRefGoogle Scholar
  100. Subramanian R, Asmawi MZ, Sadikun A (2008) Effect of andrographolide and ethanol extract of Andrographis paniculata on liver glycolytic, gluconeogenic and lipogenic enzymes in a type 2 diabetic rat model. J Pharm Biol 46:772–780CrossRefGoogle Scholar
  101. Tan ML, Sulaiman SF, Najimuddin N, Samian MR, Tengku Muhammad TS (2005) Methanolic extract of Pereskia bleo (Kunth) DC. (Cactaceae) induces apoptosis in breast carcinoma, T47-D cell line. J Ethnopharmacol 96:287–294PubMedCrossRefGoogle Scholar
  102. Tan WS, Lim SP, Goh JK, Adeline TSY (2016) Diversity and bioactivities of endophytic fungi from medicinal plant Andrographis paniculata. Ph.D thesis, Monash University, MelbourneGoogle Scholar
  103. Theantana T, Hyde KD, Lumyong S (2009) Asparaginase production by endophytic fungi from Thai medicinal plants: cytotoxicity properties. Int J Integr Biol 7:1–8Google Scholar
  104. Thirunavukkarasu N, Suryanarayanan TS, Murali TS, Ravishankar JP, Gummadi SN (2011) L-asparaginase from marine derived fungal endophytes of seaweeds. Mycosphere 2:147–155Google Scholar
  105. Ting ASY, Meon S, Kadir J, Radu S, Singh G (2009) Induced host resistance by non-pathogenic Fusarium endophyte as a potential defense mechanism in Fusarium wilt management of banana. Pest Technol 3:67–72Google Scholar
  106. Ting ASY, Mah SW, Tee CS (2011) Detection of potential volatile inhibitory compounds produced by endobacteria with biocontrol properties towards Fusarium oxysporum f. sp. cubense race 4. World J Microbiol Biotech 27:229–235CrossRefGoogle Scholar
  107. Uzma F, Narasimha MK, Srinivas C (2016) Optimization of physiological conditions for L-asparaginase production by endophytic fungi (Fusarium solani) isolated from Tinospora cordifolia (Wild.) Hook & Thomson. Eur J Exp Biol 6:37–45Google Scholar
  108. Verma N, Kumar K, Kaur G, Anand S (2007) L-asparaginase: a promising chemotherapeutic agent. Crit Rev Biotechnol 27:45–62PubMedCrossRefGoogle Scholar
  109. Vimal A, Kumar A (2017) In vitro screening and in silico validation revealed key microbes for higher production of significant therapeutic enzyme L-asparaginase. Enzym Microb Technol 98:9–17CrossRefGoogle Scholar
  110. Wahab SIA, Abdul AB, Mohan SM, Al-Zubairi AS, Elhassan IMY (2009) Biological activities of Pereskia bleo extracts. Inter J Pharmacol 5:71–75CrossRefGoogle Scholar
  111. Wang Y, Guo B, Miao Z, Tang K (2007) Transformation of taxol-producing endophytic fungi by restriction enzyme-mediated integration (REMI). FEMS Microbiol Lett 273:253–259PubMedCrossRefGoogle Scholar
  112. Wang FQ, Tong QY, Ma HR, HF X, Hu S, Ma W, Xue YB, Liu JJ, Wang JP, Song HP, Zhang JW, Zhang G, Zhang YH (2015a) Indole diketopiperazines from endophytic Chaetomium sp 88194 induce breast cancer cell apoptotic death. Sci Rep 5:9294PubMedPubMedCentralCrossRefGoogle Scholar
  113. Wang X, Wang C, Sun YT, Sun CZ, Zhang Y, Wang XH, Zhao K (2015b) Taxol produced from endophytic fungi induces apoptosis in human breast, cervical and ovarian cancer cells. Asian Pac J Cancer Prev 16:125–131PubMedCrossRefGoogle Scholar
  114. Wang MZ, Zhang W, Xu WK, Shen YM, Du LC (2016) Optimization of genome shuffling for high-yield production of the antitumor deacetylmycoepoxydiene in an endophytic fungus of mangrove plants. Appl Microbiol Biotechnol 100:7491–7498PubMedCrossRefGoogle Scholar
  115. Xiao J, Zhang Q, Gao YQ, Tang JJ, Zhang AL, Gao JM (2014) Secondary metabolites from the endophytic Botryosphaeria dothidea of Melia azedarach and their antifungal, antibacterial, antioxidant and cytotoxic activities. J Agric Food Chem 62:3584–3590PubMedCrossRefGoogle Scholar
  116. Xiong ZQ, Yang YY, Zhao N, Wang Y (2013) Diversity of endophytic fungi and screening of fungal paclitaxel producer from Anglojap yew, Taxus media. BMC Microbiol 13:71. CrossRefPubMedPubMedCentralGoogle Scholar
  117. Xu GJ, Xu LS, Wang ZT (1997) Species systematization and quality evaluation of commonly used Chinese traditional drugs. Fujian Sci Technol Press 2:650–658Google Scholar
  118. Xu L, Zhou L, Zhao W, Jiang W (2008) Recent studies on the antimicrobial compounds produced by plant endophytic fungi. Nat Prod Res Dev 20:731–740Google Scholar
  119. Xu C, Chou GX, Wang CH, Wang ZT (2012) Rare noriridoids from the roots of Andrographis paniculata. Phytochemistry 77:275–279PubMedCrossRefGoogle Scholar
  120. Yu BC, Hung CR, Chen WC, Cheng JT (2003) Antihyperglycaemic effect of andrographolide in streptozotocin-induced diabetic rats. Planta Med 69:1075–1079PubMedCrossRefGoogle Scholar
  121. Yu H, Zhang L, Li L, Zheng C, Guo L, Li W, Sun P, Qin L (2010) Recent developments and future prospects of antimicrobial metabolites produced endophytes. Microbiol Res 165:437–449PubMedPubMedCentralCrossRefGoogle Scholar
  122. Zhang XF, Tan BK (2000) Antihyperglycaemic and antioxidant properties of Andrographis paniculata in normal and diabetic rats. Clin Exp Pharmacol Physiol 27:358–363PubMedCrossRefGoogle Scholar
  123. Zhang YX, Perry K, Vinci VA, Powell K, Stemmer WP, del Cardayré SB (2002) Genome shuffling leads to rapid phenotypic improvement in bacteria. Nature 7:644–646CrossRefGoogle Scholar
  124. Zhao K, Ping WX, Zhang LN, Liu J, Lin Y, Jin T, Zhou DP (2008) Screening and breeding of high taxol producing fungi by genome shuffling. Sci China Series C 51:222–231CrossRefGoogle Scholar
  125. Zhao J, Shan T, Mou Y, Zhou L (2011) Plant-derived bioactive compounds produced by endophytic fungi. Med Chem 11:159–168Google Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Yiing Yng Chow
    • 1
  • Wei Shang Tan
    • 1
  • Adeline Su Yien Ting
    • 1
    Email author
  1. 1.School of ScienceMonash University MalaysiaBandar SunwayMalaysia

Personalised recommendations