Implication of Endophytic Metabolite and Their Derivatives in Cancer Chemotherapy: A Prospective Study

  • Pragya Mishra
  • Raghvendra Raman Mishra
  • Mallika Tiwari
  • Parjanya Shukla
  • Archana Singh
  • Hari S. Shukla


Incidence of cancer keep increasing worldwide may be due to genetic aberration, environmental effect, diet, socioeconomic factors, and various types of infections. Our previous studies revealed an association of Helicobacter pylori (H. pylori) and their species, Salmonella Typhi (S. Typhi), and Mycobacterium with various gastrointestinal tract (GI) cancers including oral, oropharyngeal, esophageal, gastric, gallbladder, pancreatic, and anal-canal cancers. We experience that poor cure rate is reported due to failure of conventional medicine, drug resistance, and failure to know the exact cause. As we are a group of oncologist and basic researcher, it is our experience that surgical procedures and chemotherapy are better adjuvant therapeutic option for cancer treatment. The area of chemotherapy is enhanced, but basic foundation is devised from natural products, which are used directly or as synthetic derivatives as stand-alone or in different combinations. Microorganisms, either bacteria or fungi that live inside plant tissue (endophytes) system, are big source of natural antimicrobial compound. It is known that endophytic alkaloids, taxoids, podophyllotoxins, etc., have an antineoplastic activity. Keeping these facts in mind, this chapter points out the active exploration and implication of endophytic metabolite and their derivatives in cancer chemotherapy in near future. Obtained data were analyzed and result showed that the endophytic metabolites may be potential source of newer cancer chemotherapeutic drugs. It concluded that in the field of cancer chemotherapy, search for novel drugs from endophytic origin is still a priority.


Pylorus Infection Endophytic Fungus Endophytic Bacterium Micrococcus Luteus Bacterial Endophyte 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors are thankful to Dr. V. C. Verma (Postdoctoral Fellow) and Prof. Gopal Nath (Head), Department of Microbiology, Banaras Hindu University, Varanasi, for his encouragement to write about such newer aspects of medical and basic science. Financial assistance from the Council of Scientific and Industrial Research, New Delhi, India (file no. 9/13(306)/2010-EMR-I), as Research associateship to RRM is gratefully acknowledged for the years 2010–2013.


Open image in new window

This article is dedicated to late Er. Shivendra Ranjan Mishra (1982–2012), younger brother of Raghvendra Raman Mishra, who lost his life in an accident of explosion in piped natural gas (PNG) at Kanpur, Uttar Pradesh, India.


  1. Bandara WMMS, Seneviratne G, Kulasooriya SA (2006) Interactions among endophytic bacteria and fungi: effects and potentials. J Biosci 31:645–650PubMedCrossRefGoogle Scholar
  2. Boopathy NS, Kathiresan K (2010) Anticancer drugs from Marine flora: an overview. J Oncol 2010:1–18CrossRefGoogle Scholar
  3. Cragg GM, Boyd MR (1996) Drug discovery and development at the National Cancer Institute: the role of natural products of plant origin. In: Balick MJ, Elisabetsky E, Laird SA (eds) Medicinal plant resources of the tropical forest. Columbia University Press, New York, pp 101–136Google Scholar
  4. Cragg GM, Newman DJ, Snader KM (1997) Natural products in drug discovery and development. J Nat Prod 60:52–60PubMedCrossRefGoogle Scholar
  5. Davis RA, Longden J, Avery VM et al (2008) The isolation, structure determination and cytotoxicity of the new fungal metabolite, trichodermamide C. Bioorg Med Chem Lett 18:2836–2839PubMedCrossRefGoogle Scholar
  6. Farber S, Diamond LK (1948) Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N Engl J Med 238:787–793PubMedCrossRefGoogle Scholar
  7. Firakova S, Sturdikova M, Muckova M (2007) Bioactive secondary metabolites produced by microorganisms associated with plants. Biologia (Bratislava) 3:251–257CrossRefGoogle Scholar
  8. Galmarini CM, Galmarini FC (2003) Multidrug resistance in cancer therapy: role of the microenvironment. Curr Opin Investig Drugs 4:1416–1421PubMedGoogle Scholar
  9. Galmarini D, Galmarini CM, Galmarini FC (2012) Cancer chemotherapy: a critical analysis of its 60 years of history. Crit Rev Oncol Hematol 84:181–199PubMedCrossRefGoogle Scholar
  10. Gilman A (1946) Therapeutic applications of chemical warfare agents. Fed Proc 5:285–292PubMedGoogle Scholar
  11. Goryluk A, Rekosz-Burlaga H, Blaszczyk M (2009) Isolation and characterization of bacterial endophytes of Chelidonium majus L. Polish J Microbiol 58:355–361Google Scholar
  12. Guimarães DO, Borges WS, Kawano CY, Ribeiro PH, Goldman GH, Nomizo A, Thiemann OH, Oliva G, Lopes NP, Pupo MT (2008) Biological activities from extracts of endophytic fungi isolated from Viguiera arenaria and Tithonia diversifolia. FEMS Immun Med Microbiol 52:134–144CrossRefGoogle Scholar
  13. Huang H, She Z, Lin Y, Vrijmoed LLP, Lin W (2007) Cyclic peptides from an endophytic fungus obtained from a mangrove leaf (Kandelia candel). J Nat Prod 70:1696–1699PubMedCrossRefGoogle Scholar
  14. Huang Z, Cai X, Shao C et al (2008) Chemistry and weak antimicrobial activities of phomopsins produced by mangrove endophytic fungus Phomopsis sp. ZSU-H76. Phytochemistry 69:604–608Google Scholar
  15. Hunt RH (1997) Peptic ulcer disease: defining the treatment strategies in the era of Helicobacter pylori. Am J Gastroenterol 92:36S–40SPubMedGoogle Scholar
  16. Jalgaonwala RE, Mahajan RT (2011) Isolation and characterization of endophytic bacteria from roots of Pongamia glabra vent. Int J Pharma Biosci 1:280–287Google Scholar
  17. Jimeno J, Faircloth G, Fern’andez Sousa-Faro JM, Scheuer P, Rinehart K (2004) New marine derived anticancer therapeutics—a journey from the sea to clinical trials. Mar Drugs 2:14–29CrossRefGoogle Scholar
  18. Kharwar RN, Verma VC, Kumar A, Gond SK, Harper JK, Hess WM, Lobkovsky E, Ma C, Ren Y, Strobel GA (2009) Javanicin, an antibacterial naphthoquinone from an endophytic. Fungus of neem, Chloridium sp. Curr Microbiol 58:233–238PubMedCrossRefGoogle Scholar
  19. Kithsiri Wijeratne EM, Paranagama PA, Marron MT, Gunatilaka MK, Arnold AE, Gunatilaka AAL (2008) Sesquiterpene quinones and related metabolites from Phyllosticta spinarum, a fungal strain endophytic in Platycladus orientalis of the Sonoran Desert. J Nat Prod 71:218–222CrossRefGoogle Scholar
  20. Konturek SJ, Starzynska T, Konturek PC, Karczewska E, Marlicz K, Lawniczak M, Jaroszewicz-Heigelman H, Bielanski W, Hartwich A, Ziemniak A, Hahn EG (2002) Helicobacter pylori and CagA status, serum gastrin, interleukin-8 and gastric acid secretion in gastric cancer. Scand J Gastroenterol 37:891–898PubMedCrossRefGoogle Scholar
  21. Lang G, Cole ALG, Blunt JW, Robinson WT, Munro MHG (2007) Excelsione, a depsidone from an endophytic fungus isolated from the New Zealand endemic tree Knightia excelsa. J Nat Prod 70:310–311PubMedCrossRefGoogle Scholar
  22. Law LW (1951) Response of a resistant variant of leukemic cells to an antagonist of pteroylglutamic acid. Proc Soc Exp Biol Med 77:340–344PubMedCrossRefGoogle Scholar
  23. Li H, Qing C, Zhao Z, Zhang Y (2005a) Screening for endophytic fungi with antitumor and antifungal activities from Chinese medicinal plants. World J Microbiol Biotechnol 21:1515–1519CrossRefGoogle Scholar
  24. Li Y, Song YC, Liu JY, Ma YM, Tan RX (2005b) Anti-Helicobacter pylori substances from endophytic fungal cultures. World J Microbiol Biotechnol 21:553–558CrossRefGoogle Scholar
  25. Li H, Wang X, Han M, Zhao Z, Wang M, Tang Q, Liu C, Kemp B, Gu Y, Shuang J, Xue Y (2012) Endophytic Bacillus subtilis ZZ120 and its potential application in control of replant diseases. Afr J Biotechnol 11:231–242Google Scholar
  26. Lin Z, Zhu T, Fang Y, Gu Q, Zhu W (2008a) Polyketides from Penicillium sp. JP-1, an endophytic fungus associated with the mangrove plant Aegiceras corniculatum. Phytochemistry 69:1273–1278PubMedCrossRefGoogle Scholar
  27. Lin ZJ, Lu ZY, Zhu TJ, Fang YC, Gu QQ, Zhu WM (2008b) Penicillenols from Penicillium sp. GQ-7, an endophytic fungus associated with Aegiceras corniculatum. Chem Pharm Bull 56:217–221PubMedCrossRefGoogle Scholar
  28. Lodewyckx C, Vangronsveld J, Porteous F, Moore ERB, Taghavi S, Mezgeay M, Lelie DV (2002) Endophytic bacteria and their potential applications. Crit Rev Plant Sci 21:583–606CrossRefGoogle Scholar
  29. Ma L, Cao YH, Cheng MH, Huang Y, Mo MH, Wang Y, Yang JZ, Yang FX (2012) Phylogenetic diversity of bacterial endophytes of Panax notoginseng with antagonistic characteristics towards pathogens of root-rot disease complex. Antonie Van Leeuwenhoek 102(3):407–408CrossRefGoogle Scholar
  30. Maa YM, Lia Y, Liua JY (2004) Anti-Helicobacter pylori metabolites from Rhizoctonia sp. Cy064, an endophytic fungus in Cynodon dactylon. Fitoterapia 75:451–456CrossRefGoogle Scholar
  31. Macías-Rubalcava ML, Hernández-Bautista BE, Jiménez-Estrada M, González MC, Glenn AE, Hanlin RT, Hernández-Ortega S, Saucedo-García A, Muria-González JM, Anaya AL (2008) Naphthoquinone spiroketal with allelochemical activity from the newly discovered endophytic fungus Edenia gomezpompae. Phytochemistry 69:1185–1196PubMedCrossRefGoogle Scholar
  32. Marshall BJ, Windsor HM (2005) The relation of Helicobacter pylori to gastric adenocarcinoma and lymphoma: pathophysiology, epidemiology, screening, clinical presentation, treatment, and prevention. Med Clin North Am 89:313–344PubMedCrossRefGoogle Scholar
  33. Matsumura Y, Maeda H (1986) A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 46:6387–6392PubMedGoogle Scholar
  34. Maurya SK, Tewari M, Mishra RR, Shukla HS (2010) Genetic aberrations in gallbladder cancer. Surg Oncol 634:1–7Google Scholar
  35. Mishra RR, Tewari M, Shukla HS (2010) Helicobacter species and pathogenesis of gallbladder cancer. Hepatobiliary Pancreat Dis Int 9:129–134PubMedGoogle Scholar
  36. Mishra RR, Tewari M, Shukla HS (2011) Helicobacter pylori and pathogenesis of gallbladder cancer. J Gas-troenterol Hepatol 26:260–266CrossRefGoogle Scholar
  37. Mishra RR, Tewari M, Shukla HS (2013) Association of Helicobacter pylori infection with inflammatory cytokine expression in patients with gallbladder cancer. Indian J Gastroenterol 32(4):232–235. doi: 10.1007/s12664-013-0321-6 PubMedCrossRefGoogle Scholar
  38. Munoz N, Correa P, Cuello C, Duque E (1968) Histological types of gastric carcinoma in high and now risk areas. Int J Cancer 3:809–818PubMedCrossRefGoogle Scholar
  39. Nomura AM, Stemmermann GN, Chyou PH (1995) Gastric cancer amount the Japanese in Hawaii. Jpn J Cancer Res 86:916–923PubMedCrossRefGoogle Scholar
  40. Oberlies NH, Kroll DJ (2004) Camptothecin and taxol: historic achievement in natural products research. J Nat Prod 67:129–135PubMedCrossRefGoogle Scholar
  41. Orlandelli RC, Alberto RN, Rubin Filho CJ, Pamphile JA (2012) Diversity of endophytic fungal community associated with Piper hispidum (Piperaceae) leaves. Genet Mole Res 11:1575–1585CrossRefGoogle Scholar
  42. Parkin DM, Bray FI, Devesa SS (2001) Cancer burden in the year 2000. The global picture. Eur J Cancer 37:S4–S66PubMedCrossRefGoogle Scholar
  43. Philips FS (1950) Recent contributions to the pharmacology of bis (2-haloethyl) amines and sulfides. J Pharmacol Exp Ther 99:281–323PubMedGoogle Scholar
  44. Pini F, Frascella A, Santopolo L, Bazzicalupo M, Biondi EG, Scotti C, Mengoni A (2012) Exploring the plant-associated bacterial communities in Medicago sativa L. BMC Microbiol 12:78PubMedCrossRefGoogle Scholar
  45. Radji M, Sumiati A, Rachmayani R, Elya B (2011) Isolation of fungal endophytes from Garcinia mangostana and their antibacterial activity. Afr J Biotechnol 10:103–107Google Scholar
  46. Ryan RP, Germaine K, Franks A, Ryan DJ, Dowling DN (2008) Bacterial endophytes: recent developments and applications. FEMS Microbiol Lett 278:1–9PubMedCrossRefGoogle Scholar
  47. Seeger DR, Smith JM Jr, Hultquist ME (1947) Antagonist for pteroylglutamic acid. J Am Chem Soc 69:2567PubMedCrossRefGoogle Scholar
  48. Silva MRO, Almeida AC, Arruda FVF, Gusmão N (2011) Endophytic fungi from Brazilian mangrove plant Laguncularia racemosa (L.) Gaertn. (Combretaceae): their antimicrobial potential. In: Mendez Vilas A (ed) Science against microbial pathogens: communicating current research and technological advances. Formatex Research Center, Badajoz, pp 1260–1266Google Scholar
  49. Smith SA, Tank DC, Boulanger L-A, Bascom-Slack CA, Eisenman K, Kingery D, Babbs B, Fenn K, Greene JS, Hann BD, Keehner J, Swift EGK, Kembaiyan V, Lee SJ, Li P, Light DY, Lin EH, Ma C, Moore E, Schorn MA, Vekhter D, Nunez PV, Strobel GA, Donoghue MJ, Strobel SA (2008) Bioactive endophytes warrant intensified exploration and conservation. PLoS ONE 8:3052CrossRefGoogle Scholar
  50. Stevens CM, Mylorie A, Auerbach C (1950) Biological action of ‘mustard gas’ compounds. Nature 166:1019–1021PubMedCrossRefGoogle Scholar
  51. Stierle A, Stierle D, Stierle D (1993) Taxol and taxane production by Taxomyces andreanae, an endophytic fungus of Pacific yew. Science 260:214–216PubMedCrossRefGoogle Scholar
  52. Strobel G, Daisy B (2003) Bioprospecting for microbial endophytes and their natural products. Microbiol Mole Biol Rev 67:491–502CrossRefGoogle Scholar
  53. Strobel G, Daisy B, Castillo U, Harper J (2004) Natural products from endophytic microorganisms. J Nat Prod 67:257–268PubMedCrossRefGoogle Scholar
  54. Sun L, Qiu F, Zhang X, Dai X, Dong X, Song W (2008) Endophytic bacterial diversity in rice (Oryza sativa L.) roots estimated by 16S rDNA sequence analysis. Microb Ecol 55:415–424PubMedCrossRefGoogle Scholar
  55. Taghavi S, Garafola C, Monchy S, Newman L, Hoffman A, Weyens N, Barac T, Vangronsveld J, Lelie DV (2009) Genome survey and characterization of endophytic bacteria exhibiting a beneficial effect on growth and development of poplar trees. Appl Environ Microbiol 75:748–757PubMedCrossRefGoogle Scholar
  56. Tansuwan S, Pornpakakul S, Roengsumran S, Petsom A, Muangsin N, Sihanonta P, Chaichit N (2007) Antimalarial benzoquinones from an endophytic fungus, Xylaria sp. J Nat Prod 70:1620–1623PubMedCrossRefGoogle Scholar
  57. Tewari M, Mishra RR, Kumar V, Kar AG, Shukla HS (2008a) Isolated tuberculosis of the ampulla of vater masquerading as periampullary carcinoma: a case report. J Pancreas 10:16001–16003Google Scholar
  58. Tewari M, Kumar V, Mishra RR, Kumar M, Shukla HS (2008b) Is there a role for cholecystectomy in gallbladder carcinoma discovered to be unrespectable for cure at laparotomy? World J Surg 32:2683–2687PubMedCrossRefGoogle Scholar
  59. Tewari M, Kumar V, Mishra RR, Shukla HS (2009) Gallbladder carcinoid masquerading as gallbladder carcinoma: a case report. Hepato Pancreat Dis Int 8:121–123Google Scholar
  60. Tewari M, Mishra RR, Shukla HS (2010) Salmonella typhi and gallbladder carcinoma: report from an endemic region. Hepatobiliary Pancreat Dis Int 9:458–464Google Scholar
  61. Tewari M, Sahai S, Mishra RR, Shukla SK, Shukla HS (2012) Dendritic cell therapy in advanced gastric cancer: a promising new hope? Surg Oncol 21:164–171PubMedCrossRefGoogle Scholar
  62. Tewari M, Agarwal A, Mishra RR, Meena RN, Shukla HS (2013a) Epigenetic changes in carcinogenesis of gallbladder. Indian J Surg Oncol. doi: 10.1007/s13193-013-0240-0,1-10 Google Scholar
  63. Tewari M, Srivastava AK, Mishra RR, Kumar M, Shukla HS (2013) HER2 expression in gastric and gastroesophageal cancer: report from a tertiary care hospital in North India. Indian J Surg. doi: 10.1007/s12262-013-0871-y, 1–5
  64. Uemura N, Okamoto S, Yamamoto S (2002) Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 345:784–789CrossRefGoogle Scholar
  65. Verma VC (ed) (2012) Microbial endophyte of neem: a biotechnological perspective. LAP Lambert Academic Publishing Gmbh & Co Kg, Heinrich-Bocking–strr. 6–8, 66121, Saarbrücken, GermanyGoogle Scholar
  66. Wadstrom T, Hanninen ML (1999) Helicobacter in the digestive tract. Curr Opin Gastroenterol 15:S53–S56CrossRefGoogle Scholar
  67. Xu F, Zhang Y, Wang J, Pang J, Huang C, Wu X, She Z, Vrijmoed LLP, Jones EBG, Lin Y (2008) Benzofuran derivatives from the mangrove endophytic fungus Xylaria sp. J Nat Prod 71:1251–1253PubMedCrossRefGoogle Scholar
  68. Zhang HW, Song YC, Tan RX (2001) Biology and chemistry of endophytes. Nat Prod Rep 18:448CrossRefGoogle Scholar
  69. Zhang Y, Ming LX, Wang BG (2007) Nigerasperones A-C, new monomeric and dimeric naphtho-γ-pyrones from a marine alga-derived endophytic fungus Aspergillus niger EN-13. J Antibiot 60:204–210PubMedCrossRefGoogle Scholar
  70. Zhang J, Tao L, Liang Y, Chen L, Mi Y, Zheng L, Wang F, She Z, Lin Y, To KKW, Fu L (2010) Anthracenedione derivatives as anticancer agents isolated from secondary metabolites of the mangrove endophytic fungi. Mar Drugs 8:1469–1481PubMedCrossRefGoogle Scholar
  71. Zhao J, Zhou L, Wang J, Shan T, Zhong L, Liu X, Gao X (2010) Méndez-Vilas A (Ed) FORMATEX Madrid (Spain) Endophytic fungi for producing bioactive compounds originally from their host plants. Curr Res Technol Edu Topics Appl Microbiol Microb Biotechnol 1:567–576Google Scholar
  72. Zhu B, Liu H, Tian WX, Fan XY, Li B, Zhou XP, Jin GL, Xiea GL (2012) Sequence of Stenotrophomonas maltophilia RR-10, isolated as an endophyte from rice root. J Bacteriol 194:1280–1281PubMedCrossRefGoogle Scholar
  73. Zinniel DK, Lambrecht P, Harris NB, Feng Z, Kuczmarski D, Higley P, Ishimaru CA, Arunakumari A, Barletta RG, Vidaver AK (2002) Isolation and characterization of endophytic colonizing bacteria from agronomic crops and prairie plants. Appl Environ Microbiol 68:2198–2208PubMedCrossRefGoogle Scholar

Copyright information

© Springer India 2014

Authors and Affiliations

  • Pragya Mishra
    • 1
  • Raghvendra Raman Mishra
    • 2
  • Mallika Tiwari
    • 3
  • Parjanya Shukla
    • 4
  • Archana Singh
    • 5
  • Hari S. Shukla
    • 3
  1. 1.Ranjan Physiology and Biochemistry Laboratory, Department of Botany, Centre of Food TechnologyUniversity of AllahabadAllahabadIndia
  2. 2.Department of Microbiology, Institute of Medical SciencesBanaras Hindu UniversityVaranasiIndia
  3. 3.Department of Surgical Oncology, Institute of Medical SciencesBanaras Hindu UniversityVaranasiIndia
  4. 4.Department of Pharmaceutical Sciences, Faculty of Health ScienceSam Higginbottom Institute of Agriculture Technology and Sciences – Deemed UniversityAllahabadIndia
  5. 5.Department of Botany, Faculty of ScienceBanaras Hindu UniversityVaranasiIndia

Personalised recommendations