Anti Cancer Agents from Microbes



Microbial diversity has a pivotal role in discovering antibiotics and anticancer agents. Anticancer drug discovery has seen a lot of technological development in the last few years. Screening for cancer drugs has moved forward from the traditional cell-based screening that looks for antiproliferative effects to specific approach to scan for molecules that can target prominent proteins or pathways in cancer. These employed technologies will help to find molecules selective for cancer cells while avoiding normal cells, thus improving efficacy and selectivity in cancer therapy. Microbial diversity has a lot to offer in terms of drug discovery. Among the different groups of microorganisms, members of actinomycetes have provided more number of anticancer compounds and other bioactive metabolites. Symbiotic microorganisms associated with higher marine organisms are also identified as a potential source of novel anticancer lead compounds. Metagenomic approaches to screen uncultivable microorganisms also offer a novel source for the invention of new therapeutic metabolites.


Cancer Microbes Streptomyces Anticancer 


  1. Alberts DS, Garcia D, Mason-Liddil N (1991) Cisplatin in advanced cancer of the cervix: an update. Semin Oncol 18:11–24PubMedGoogle Scholar
  2. Asolkar RN, Maskey RP, Helmke E, Laatsch H (2002) Chalcomycin B, a new macrolide antibiotic from the marine isolate Streptomyces sp. B7064. J Antibiot 55:893–898CrossRefPubMedGoogle Scholar
  3. Basu A, Lazo JS (1992) Sensitization of human cervical carcinoma cells to cis-diamminedichloroplatinum (II) by bryostatin 1. Cancer Res 52:3119–3124PubMedGoogle Scholar
  4. Becerro MA, Goetz G, Paul VJ, Scheuer PJ (2001) Chemical defenses of the sacoglossan mollusk Elysia rufescens and its host alga Bryopsis sp. J Chem Ecol 27:2287–2299CrossRefPubMedGoogle Scholar
  5. Beck TP, Kirsh EJ, Chmura SJ, Kovar DA, Chung T, Rinker-Schaeffer CW, Stadler WM (1999) In vitro evaluation of calphostin C as a novel agent for photodynamic therapy of bladder cancer. Urology 154:573–577CrossRefGoogle Scholar
  6. Berdy J (2005) Bioactive microbial metabolites. J Antibiot 58:1–26CrossRefPubMedGoogle Scholar
  7. Betz C, Hall MN (2013) Where is mTOR and what is it doing there? J Cell Biol 203:563–574CrossRefPubMedPubMedCentralGoogle Scholar
  8. Bruns RF, Miller FD, Merriman RL, Howbert JJ, Heath WF, Kobayashi E, Takahashi I, Tamaoki T, Nakano H (1991) Inhibition of protein kinase C by calphostin C is light-dependent. Biochem Biophys Res Commun 176:288–293CrossRefPubMedGoogle Scholar
  9. Cardenas ME, Sanfridson A, Cutler NS, Heitman J (1998) Signal-transduction cascades as targets for therapeutic intervention by natural products. Trends Biotechnol 16:427–433CrossRefPubMedGoogle Scholar
  10. Carte BK (1966) Biomedical potential of marine natural products. Bioscience 46:271–286Google Scholar
  11. Cheng YQ, Tang GL, Shen B (2003) Type I polyketide synthase requiring a discrete acyltransferase for polyketide biosynthesis. Proc Natl Acad Sci U S A 100:3149–3154CrossRefPubMedPubMedCentralGoogle Scholar
  12. Chiarini A, Whitfield JF, Armato U, Dal Pra I (2006) VP-16 (etoposide) and calphostin C trigger different nuclear but akin cytoplasmic patters of changes in the distribution and activity of protein kinase C-ßI in polyomavirus-transformed pyF111 rat fibroblasts. Int J Mol Med 17:111–120PubMedGoogle Scholar
  13. Choi J, Chen J, Schreiber SL, Clardy J (1996) Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science 273:239–242CrossRefPubMedGoogle Scholar
  14. Cox AD, Der CJ (1997) Farnesyltransferase inhibitors and cancer treatment: targeting simply Ras? Biochim Biophys Acta 1333:51–71Google Scholar
  15. Dal Pra I, Whitfield JF, Chiarini A, Armato U (2000) Increased activity of the protein kinase-‰ holoenzyme in the cytoplasmic particulate fraction precedes activation of caspases in the polyomavirus- transformed pyF111 rat fibroblasts exposed to calphostin C or topoisomerase II inhibitors. Exp Cell Res 255:171–183CrossRefPubMedGoogle Scholar
  16. Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, Cuny GD, Mitchison TJ, Moskowitz MA, Yuan J (2005) Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 1:112–119CrossRefPubMedGoogle Scholar
  17. Diwu Z, Lown JW (1993) Photosensitization with anticancer agents. 15. Perylenequinoid pigments as potential photodynamic therapeutic agents: formation of semiquinone radicals and reactive oxygen species on illumination. J Photochem Photobiol 18:131–143CrossRefGoogle Scholar
  18. Ferrer M, Beloqui A, Timmis KN, Golyshin PN (2009) Metagenomics for mining new genetic resources of microbial communities. J Mol Microbiol Biotechnol 16:109–123CrossRefPubMedGoogle Scholar
  19. Fingar DC, Richardson CJ, Tee AR, Cheatham L, Tsou C, Blenis J (2004) mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol 24:200–216CrossRefPubMedPubMedCentralGoogle Scholar
  20. Fleming A (1929) On the antibacterial action of cultures of Penicillium, with special reference to their use in the isolation of B. influenzae. Br J Exp Pathol 10:226–236PubMedCentralGoogle Scholar
  21. Gebauer F, Hentze MW (2004) Molecular mechanisms of translational control. Nat Rev Mol Cell Biol 5:827–835CrossRefPubMedGoogle Scholar
  22. Gerner EW, Meyskens FL (2004) Polyamines and cancer: old molecules, new understanding. Nat Rev Cancer 4:781–792CrossRefPubMedGoogle Scholar
  23. Gillespie DE, Brady SF, Bettermann AD, Cianciotto NP, Liles MR, Rondon MR, Clardy J, Goodman RM, Handelsman J (2002) Isolation of antibiotics turbomycin A and B from a metagenomic library of soil microbial DNA. Appl Environ Microbiol 68:4306–4310CrossRefGoogle Scholar
  24. Gingras AC, Raught B, Sonenberg N (1999) eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu Rev Biochem 68:913–963CrossRefPubMedGoogle Scholar
  25. Gokhale RS, Sankaranarayanan R, Mohanty D (2007) Versatility of polyketide synthases in generating metabolic diversity. Curr Opin Struct Biol 17:736–743CrossRefPubMedGoogle Scholar
  26. Goldberg IH, Rabinowitz M, Reich E (1962) Basis of actinomycin action, i. DNA binding and inhibition of RNA-polymerase synthetic reactions by actinomycin. Proc Natl Acad Sci U S A 48:2094–2101CrossRefPubMedPubMedCentralGoogle Scholar
  27. Grever MR, Lozanski G (2011) Modern strategies for hairy cell leukaemia. J Clin Oncol 29:583–590CrossRefPubMedGoogle Scholar
  28. Haddadin R (2010) Combination of manumycin A and Mebendazole in human breast cancer cell lines. A dissertation presented to the Faculty of the Department of Pharmacological and Pharmaceutical Sciences College of Pharmacy, University of HoustonGoogle Scholar
  29. Hale K, Hummersone M, Manaviazar S, Frigerio M (2002) The chemistry and biology of the bryostatin antitumour macrolides. Nat Prod Rep 19:413–453CrossRefPubMedGoogle Scholar
  30. Hara M, Akasaka K, Akinaga S, Okabe M, Nakano H, Gomez R, Wood D, Uh M, Tamanoi F (1993) Identification of Ras farnesyltransferase inhibitors by microbial screening. Proc Natl Acad Sci U S A 90:2281–2285CrossRefPubMedPubMedCentralGoogle Scholar
  31. Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18:1926–1945CrossRefPubMedGoogle Scholar
  32. Hill RT, Enticknap J, Rao KV, Hamann MT (2007) Kahalalide-producing bacteria. US patent 20070196901Google Scholar
  33. Jeandet P, Vasserot Y, Chastang T, Courot E (2013). Engineering microbial cells for the biosynthesis of natural compounds of pharmaceutical significance. BioMed Research International. Article ID 780145. doi: 10.1155/2013/780145
  34. 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 2:14–29CrossRefPubMedCentralGoogle Scholar
  35. Johnston JB (2011) Mechanism of action of pentostatin and cladribine in hairy cell leukaemia. Leuk Lymphoma 52:43–45CrossRefPubMedGoogle Scholar
  36. Kathiresan K, Duraisamy A (2005) Current issue of marine microbiology. ENVIS Centre Newsletters 4:3–5Google Scholar
  37. Kathiresan K, Nabeel MA, Manivannan S (2008) Bioprospecting of marine organisms for novel bioactive compounds. Sci Trans Environ Technov 1:107–120Google Scholar
  38. Kaul A, Maltese WA (2009) Killing of cancer cells by the photoactivatable protein kinase C inhibitor, calphostin C, involves induction of endoplasmic reticulum stress. Neoplasia 11:823–834CrossRefPubMedPubMedCentralGoogle Scholar
  39. Kodama M, Ogata T, Sato S (1988) Bacterial production of saxitoxin. Agric Biol Chem 52:1075–1077Google Scholar
  40. Kortmansky J, Schwartz GK (2003) Bryostatin-1: a novel PKC inhibitor in clinical development. Cancer Investig 21:924–936CrossRefGoogle Scholar
  41. Nakatogawa H, Suzuki K, Kamada Y, Ohsumi Y (2009) Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat Rev Mol Cell Biol 10:458–467CrossRefPubMedGoogle Scholar
  42. Nelson TJ, Alkon DL (2009) Neuroprotective versus tumorigenic protein kinase C activators. Trends Biochem Sci 34:136–145CrossRefPubMedGoogle Scholar
  43. Newman DJ, Cragg GM (2007) Natural products as sources of new drugs over the last 25 years. J Nat Prod 70:461–477CrossRefPubMedGoogle Scholar
  44. Norbury CJ, Hickson ID (2001) Cellular responses to DNA damage. Annu Rev Pharmacol Toxicol 41:367–401CrossRefPubMedGoogle Scholar
  45. Olano C, Méndez C, Salas JA (2009) Antitumor compounds from actinomycetes: from gene clusters to new derivatives by combinatorial biosynthesis. Nat Prod Rep 26:628–660CrossRefPubMedGoogle Scholar
  46. Pace NR, Stahl DA, Lane DJ, Olsen GJ (1985) Analyzing natural microbial populations by rRNA sequences. Adv Microb Ecol 51:4–12Google Scholar
  47. Perry RP (1963) Selective effects of actinomycin D on the intracellular distribution of RNA synthesis in tissue culture cells. Exp Cell Res 29:400–406CrossRefGoogle Scholar
  48. Pestova TV et al (2001) Molecular mechanisms of translation initiation in eukaryotes. Proc Natl Acad Sci U S A 98:7029–7036CrossRefPubMedPubMedCentralGoogle Scholar
  49. Pettit RK (2004) Soil DNA libraries for anticancer drug discovery. Cancer Chemother Pharmacol 54:1–6Google Scholar
  50. Piel J, Hui D, Wen G, Butzke D, Platzer M, Fusetani N, Matsunaga S (2004) Antitumor polyketide biosynthesis by an uncultivated bacterial symbiont of the marine sponge Theonella swinhoei. Proc Natl Acad Sci U S A 101:16222–16227CrossRefPubMedPubMedCentralGoogle Scholar
  51. Reich E, Goldberg I (1964) Actinomycin and nucleic acid function. Prog Nucleic Acid Res Mol Biol 3:183–234CrossRefPubMedGoogle Scholar
  52. Sačková V, Kuliková L, Kello M, Uhrinová I, Fedoročko P (2011) Enhanced Antiproliferative and apoptotic response of HT-29 adenocarcinoma cells to combination of Photoactivated Hypericin and farnesyltransferase inhibitor manumycin A. Int J Mol Sci 1:8388–8405CrossRefGoogle Scholar
  53. Schirmer A, Gadkari R, Reeves CD, Ibrahim F, DeLong EF, Hutchinson CR (2005) Metagenomic analysis reveals diverse Polyketide synthase gene clusters in microorganisms associated with the marine sponge Discodermia dissolute. Appl Environ Microbiol 71:4840–4849CrossRefPubMedPubMedCentralGoogle Scholar
  54. Schloss PD, Handelsman J (2003) Biotechnological prospects from metagenomics. J Curr Opin Biotechnol 14:303–310CrossRefGoogle Scholar
  55. Schwartsmann G et al (2002) Anticancer drug discovery and development throughout the world. J Clin Oncol 18:47–59Google Scholar
  56. She M, Yang H, Sun L, Yeung SC (2006) Redox control of manumycin A-induced apoptosis in anaplastic thyroid cancer cells: involvement of the xenobiotic apoptotic pathway. Cancer Biol Ther 5:275–280CrossRefPubMedGoogle Scholar
  57. Simidu U, Kita-Tsukamoto K, Yasumoto T, Yotsu M (1990) Taxonomy of four marine bacterial strains that produce tetrodotoxin. Int J Syst Bacteriol 40:331–336CrossRefPubMedGoogle Scholar
  58. Sobell HM, Jain SC, Sakore TD, Nordman CE (1971) Stereochemistry of actinomycin—DNA binding. Nature 231:200–205Google Scholar
  59. Thoreen CC et al (2009) An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 284:8023–8032CrossRefPubMedPubMedCentralGoogle Scholar
  60. Ventura M, Canchaya C, Tauch A, Chandra G, Fitzgerald GF, Chater KF, Van SD (2007) Genomics of actinobacteria: tracing the evolutionary history of an ancient phylum. Microbiol Mol Biol Rev 71:495–548CrossRefPubMedPubMedCentralGoogle Scholar
  61. Wang W, Macaulay RJ (1999) Apoptosis of medulloblastoma cells in vitro follows inhibition of farnesylation using manumycin A. Int J Cancer 82:430–434CrossRefPubMedGoogle Scholar
  62. Williams PG, Miller ED, Asolkar RN, Jensen PR, Fenical W (2007) Arenicolides AC, 26- membered ring macrolides from the marine actinomycete Salinispora arenicola. J Org Chem 72:5025–5034CrossRefPubMedPubMedCentralGoogle Scholar
  63. Wullschleger S, Loewith R, Hall MN (2006) TOR signalling in growth and metabolism. Cell 124:471–484CrossRefPubMedGoogle Scholar
  64. Yang W, Del VK, Urano J, Mitsuzawa H, Tamanoi F (1997) Advances in the development of farnesyltransferase inhibitors: substrate recognition by protein farnesyltransferase. J Cell Biochem 27:12–19CrossRefGoogle Scholar
  65. Zhou JM, Zhu XF, Pan QC, Liao DF, Li ZM, Liu ZC (2003) Manumycin induces apoptosis in human hepatocellular carcinoma HepG2 cells. Int J Mol Med 12:955–959PubMedGoogle Scholar
  66. Zimmermann K, Engeser M BJW, Munro MH, Piel J (2009) Pederintype pathways of uncultivated bacterial symbionts: analysis of o-methyltransferases and generation of a biosynthetic hybrid. J Am Chem Soc 131:2780–2781CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  1. 1.Microbiology DivisionJawaharlal Nehru Tropical Botanical Garden and Research InstituteThiruvananthapuramIndia
  2. 2.Cancer Research ProgramRajiv Gandhi Centre for BiotechnologyThiruvananthapuramIndia

Personalised recommendations