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Fungal metabolites: structural diversity as incentive for anticancer drug development

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Abstract

Natural products play an important role in the development of anticancer drugs. To date, predominantly metabolites from plants and bacteria served as lead structures for anticancer agents. Fungal metabolites and derivatives thereof are much less investigated for their potential in cancer therapy. There are, however, some promising candidates derived from fungi in clinical phases I and II studies. This review gives an overview on the role of natural products in cancer therapy and summarises some of the latest results of our group in this area.

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References

  • Albini A, Sporn MB (2007) The tumour microenvironment as a target for chemoprevention. Nat Rev Cancer 7:139–147

    Article  CAS  PubMed  Google Scholar 

  • Altmann KH, Gertsch J (2007) Anticancer drugs from nature—natural products as a unique source of new microtubule—stabilizing agents. Nat Prod Rep 24:327–357

    Article  CAS  PubMed  Google Scholar 

  • Anchel M, Hervey A, Robbins WJ (1950) Antibiotic substances from basidiomycetes. VII. Clitocybe illudens. Proc Natl Acad Sci USA 36:300–305

    Article  CAS  PubMed  Google Scholar 

  • Anchel M, McMorris TC, Singh P (1970) The biogenesis of illudin S and M in clitocybe illudens. Phytochemistry 9:2339–2343

    Article  CAS  Google Scholar 

  • Arico-Muendel CC, Benjamin DR, Caiazzo TM, Centrella PA, Contonio BD, Brooke D, Cook CM, Doyle EG, Hannig G, Labenski MT, Searle LL, Lind K, Morgan BA, Olson G, Paradise CL, Self C, Skinner SR, Sluboski B, Svendsen JL, Thompson CD, Westlin W, White KF (2009) Carbamate analogues of fumagillin as potent, targeted inhibitors of methionine aminopeptidase-2. J Med Chem 52:8047–8056

    Article  CAS  PubMed  Google Scholar 

  • Baekelandt M (2002) Irofulven. Curr Opin Investig Drugs 3:1517–1526

    CAS  PubMed  Google Scholar 

  • Bernier SG, Taghizadeh N, Thompson CD, Westlin WF, Hannig G (2005a) Methionine aminopeptidases type I and type II are essential to control cell proliferation. J Cell Biochem 95:1191–1203

    Article  CAS  PubMed  Google Scholar 

  • Bernier SG, Westlin WF, Hannig G (2005b) Fumagillin class inhibitors of methionine aminopeptidase-2. Drugs Future 30:497–508

    Article  CAS  Google Scholar 

  • Birch AJ, Hussain SF (1969) Studies in relation to biosynthesis. Part XXXVIII. A preliminary study of fumagillin. J Chem Soc (C):1473–1474

  • Bringmann G, Lang G, Mühlbacher J, Schaumann K, Steffens S, Rytik PG, Hentschel U, Morschhäuser J, Müller WEG (2003) Sorbicillactone A: a structurally unprecedented bioactive novel-type alkaloid from a sponge-derived fungus. Prog Mol Subcell Biol 37:231–253

    CAS  PubMed  Google Scholar 

  • Bringmann G, Lang G, Gulder TAM, Tsuruta H, Mühlbacher J, Maksimenka K, Steffens S, Schaumann K, Stöhr R, Wiese J, Imhoff JF, Perović-Ottstadt S, Boreiko O, Müller WEG (2005) The first sorbicillinoid alkaloids, the antileukemic sorbicillactones A and B, from a sponge-derived Penicillium chrysogenum strain. Tetrahedron 61:7252–7265

    Article  CAS  Google Scholar 

  • Bugni TS, Ireland CM (2004) Marine-derived fungi: a chemically and biologically diverse group of microorganisms. Nat Prod Rep 21:143–163

    Article  CAS  PubMed  Google Scholar 

  • Butler MS (2008) Natural products to drugs: natural product-derived compounds in clinical trials. Nat Prod Rep 25:475–516

    Article  CAS  PubMed  Google Scholar 

  • Chun E, Han CK, Yoon JH, Sim TB, Kim YK, Lee KY (2005) Novel inhibitors targeted to methionine aminopeptidase 2 (MetAP2) strongly inhibit the growth of cancers in xenografted nude model. Int J Cancer 114:124–130

    Article  CAS  PubMed  Google Scholar 

  • Conlin A, Fornier M, Hudis C, Kar S, Kirkpatrick P (2007) Ixabepilone. Nat Rev Drug Discov 6:953–954

    Article  CAS  Google Scholar 

  • Cragg GM, Newman DJ (2004) A tale of two tumor targets: topoisomerase I and tubulin. The wall and wani contribution to cancer chemotherapy. J Nat Prod 67:232–244

    Article  CAS  PubMed  Google Scholar 

  • Cragg GM, Newman DJ (2009) Nature: a vital source of leads for anticancer drug development. Phytochem Rev 8:313–331

    Article  CAS  Google Scholar 

  • Deng Y, Chin Y-W, Chai H, Keller WJ, Kinghorn AD (2007) Anthraquinones with quinone reductase-inducing activity and Benzophenones from Morinda citrifolia (Noni) roots. J Nat Prod 70:2049–2052

    Article  CAS  PubMed  Google Scholar 

  • Escargueil A, Poindessous V, Soares DG, Sarasin A, Cook PR, Larsen AK (2008) Influence of irofulven, a transcription-coupled repair-specific antitumor agent, on RNA polymerase activity, stability and dynamics in living mammalian cells. J Cell Sci 121:1275–1283

    Article  CAS  PubMed  Google Scholar 

  • Eyberger AL, Dondapati R, Porter JR (2006) Endophyte fungal isolates from Podophyllum peltatum produce podophyllotoxin. J Nat Prod 69:1121–1124

    Article  CAS  PubMed  Google Scholar 

  • Gerhäuser C, Klimo K, Heiss E, Neumann I, Gamal-Eldeen A, Knauft J, Liu G-Y, Sitthimonchai S, Frank N (2003) Mechanism-based in vitro screening of potential cancer chemopreventive agents. Mutat Res 523:163–172

    PubMed  Google Scholar 

  • Gong J, Vaidyanathan VG, Yu X, Kensler TW, Peterson LA, Sturla SJ (2007) Depurinating acylfulvene-DNA adducts: characterizing cellular chemical reactions of a selective antitumor agent. J Am Chem Soc 129:2101–2111

    Article  CAS  PubMed  Google Scholar 

  • Greenwald P (2001) From carcinogenesis to clinical interventions for cancer prevention. Toxicology 166:37–45

    Article  CAS  PubMed  Google Scholar 

  • Greve H, Schupp PJ, Eguerva E, Kehraus S, Kelter G, Maier A, Fiebig H-H, König GM (2008) Apralactone A and a new stereochemical class of curvularins from the marine fungus Curvularia sp. Eur J Org Chem:5085–5092

  • Griffith EC, Su Z, Turk BE, Chen S, Chang YH, Wu Z, Biemann K, Liu JO (1997) Methionine aminopeptidase (type 2) is the common target for angiogenesis inhibitors AGM-1470 and ovalicin. Chem Biol 4:461–471

    Article  CAS  PubMed  Google Scholar 

  • Griffith EC, Su Z, Niwayama S, Ramsay CA, Chang YH, Liu JO (1998) Molecular recognition of angiogenesis inhibitors fumagillin and ovalicin by methionine aminopeptidase 2. Proc Natl Acad Sci USA 95:15183–15188

    Article  CAS  PubMed  Google Scholar 

  • Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  CAS  PubMed  Google Scholar 

  • Heron MP, Hoyert DL, Murphy SL, Xu JQ, Kochanek KD, Tejada-Vera B (2009) Deaths: final data for 2006. Natl Vit Stat Rep 57:1–136

    Google Scholar 

  • Herzig M, Arnett B, MacDonald JR, Woynarowski JM (1999) Drug uptake and cellular targets of Hydroxymethylacylfulvene (HMAF). Biochem Pharmacol 58:217–225

    Article  CAS  PubMed  Google Scholar 

  • Ingber D, Fujita T, Kishimoto S, Sudo K, Kanamaru T, Brem H, Folkman J (1990) Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumor growth. Nature 348:555–557

    Article  CAS  PubMed  Google Scholar 

  • Kanoh K, Kohno S, Asari T, Harada T, Katada J, Muramatsu M, Kawashima H, Sekiya H, Uno I (1997) (-)-Phenylahistin: a new mammalian cell cycle inhibitor produced by Aspergillus ustus. Bioorg Med Chem Lett 7:2847–2852

    Article  CAS  Google Scholar 

  • Kanoh K, Kohno S, Katada J, Hayashi Y, Muramatsu M, Uno I (1999a) Antitumor activity of phenylahistin in vitro and in vivo. Biosci Biotechnol Biochem 63:1130–1133

    Article  CAS  PubMed  Google Scholar 

  • Kanoh K, Kohno S, Katada J, Takahashi J, Uno I (1999b) (-)-Phenylahistin arrests cells in mitosis by inhibiting tubulin polymerization. J Antibiot 52:134–141

    CAS  PubMed  Google Scholar 

  • Karin M (2006) Nuclear factor-kappa B in cancer development and progression. Nature 441:431–436

    Article  CAS  PubMed  Google Scholar 

  • Kralj A, Kehraus S, Krick A, Eguereva E, Kelter G, Maurer M, Wortmann A, Fiebig H-H, König GM (2006) Arugosins G and H: prenylated polyketides from the marine-derived fungus Emericella nidulans var. acristata. J Nat Prod 69:995–1000

    Article  CAS  PubMed  Google Scholar 

  • Krick A, Kehraus S, Gerhäuser C, Klimo K, Nieger M, Maier A, Fiebig H-H, Atodiresei I, Raabe G, Fleischhauer J, König GM (2007) Potential cancer chemopreventive in vitro activities of monomeric xanthone derivatives from the marine algicolous fungus Monodictys putredinis. J Nat Prod 70:353–360

    Article  CAS  PubMed  Google Scholar 

  • Lanternier F, Boutboul D, Menotti J, Chandesris MO, Sarfati C, Mamzer Bruneel MF, Calmus Y, Mechaï F, Viard JP, Lecuit M, Bougnoux ME, Lortholary O (2009) Microsporidiosis in solid organ transplant recipients: two Enterocytozoon bieneusi cases and review. Transpl Infect Dis 11:83–88

    Article  CAS  PubMed  Google Scholar 

  • Liu S, Widom J, Kemp CW, Crews CM, Clardy J (1998) Structure of human methionine aminopeptidase-2 complexed with fumagillin. Science 282:1324–1327

    Article  CAS  PubMed  Google Scholar 

  • Lu J, Chong CR, Hu X, Liu JO (2006) Fumarranol, a rearranged fumagillin analogue that inhibits angiogenensis in vivo. J Med Chem 49:5645–5648

    Article  CAS  PubMed  Google Scholar 

  • Mani S, Ghalib M, Goel S (2007) Ixabepilone. Drugs Future 32:1033–1039

    Article  CAS  Google Scholar 

  • McMorris TC (1999) Discovery and development of sesquiterpenoid derived Hydroxymethylacylfulvene: a new anticancer drug. Bioorg Med Chem 7:881–886

    Article  CAS  PubMed  Google Scholar 

  • McMorris TC, Anchel M (1965) Fungal metabolites. The structures of the novel sesquiterpenoids illudin-S and -M. J Am Chem Soc 87:1594–1600

    Article  CAS  PubMed  Google Scholar 

  • McMorris TC, Kelner MJ, Wang W, Yu J, Estes LA, Taetle R (1996) (Hydroxymethyl)acylfulvene: an illudin derivative with superior antitumor properties. J Nat Prod 59:896–899

    Article  CAS  PubMed  Google Scholar 

  • Misiek M, Hoffmeister D (2007) Fungal genetics, genomics, and secondary metabolites in pharmaceutical sciences. Planta Med 73:103–115

    Article  CAS  PubMed  Google Scholar 

  • Mohamed IE, Gross H, Pontius A, Kehraus S, Krick A, Kelter G, Maier A, Fiebig H-H, König GM (2009) Epoxyphomalin A and B, potent cytotoxic prenylated polyketides from the marine-derived fungus Phoma sp. Org Lett 11:5014–5017

    Article  CAS  PubMed  Google Scholar 

  • Neumann K, Kehraus S, Gütschow M, König GM (2009) Cytotoxic and HLE-inhibitory tetramic acid derivatives from marine-derived fungi. Nat Prod Comms 4:347–354

    CAS  Google Scholar 

  • Newman DJ, Cragg GM (2006) Natural products from marine invertebrates and microbes as modulators of antitumor targets. Curr Drug Targets 7:279–304

    Article  CAS  PubMed  Google Scholar 

  • Newman DJ, Cragg GM (2007) Natural products as sources of new drugs over the last 25 years. J Nat Prod 70:461–477

    Article  CAS  PubMed  Google Scholar 

  • Newman DJ, Cragg GM, Snader KM (2000) The influence of natural products upon drug discovery. Nat Prod Rep 17:215–234

    Article  CAS  PubMed  Google Scholar 

  • Nicholson B, Lloyd GK, Miller BR, Palladino MA, Kiso Y, Hayashi Y, Neuteboom STC (2006) NPI-2358 is a tubulin-depolymerization agent: in vitro evidence for activity as a tumor vascular-disrupting agent. Anticancer drugs 17:25–31

    Article  CAS  PubMed  Google Scholar 

  • Niederlaender E (2006) Statistics in focus—theme 3, population and social conditions. Offical Publications of the European Communities, Luxemburg

    Google Scholar 

  • Pontius A, Krick A, Kehraus S, Brun R, König GM (2008a) Antiprotozoal activities of heterocyclic-substituted xanthones from the marine-derived fungus Chaetomium sp. J Nat Prod 71:1579–1584

    Article  CAS  PubMed  Google Scholar 

  • Pontius A, Krick A, Kehraus S, Foegen SE, Müller M, Klimo K, Gerhäuser C, König GM (2008b) Noduliprevenone: a novel heterodimeric chromanone with cancer chemopreventive potential. Chem Eur J 14:9860–9863

    Article  CAS  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 68:1717–1719

    Article  CAS  PubMed  Google Scholar 

  • Schwartsmann G, Ratain MJ, Cragg GM, Wong JE, Saijo N, Parkinson DR, Fujiwara Y, Pazdur R, Newman DJ, Dagher R, Di Leone L (2002) Anticancer drug discovery and development throughout the world. J Clin Oncol 20:47s–49s

    CAS  PubMed  Google Scholar 

  • Sellars JD, Steel PG (2007) Advances in the synthesis of aryltetralin lignan lactones. Eur J Org Chem:3815–3828

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

    Article  CAS  PubMed  Google Scholar 

  • Strobel G, Daisy B (2003) Bioprospecting for microbial endophytes and their natural products. Microbiol Mol Biol Rev 67:491–502

    Article  CAS  PubMed  Google Scholar 

  • Strobel G, Daisy B, Castillo U, Harper J (2004) Natural products from endophytic microorganisms. J Nat Prod 67:257–268

    Article  CAS  PubMed  Google Scholar 

  • Talalay P, Fahey JW, Holtzclaw WD, Prestera T, Zhang Y (1995) Chemoprotection against cancer by phase 2 enzyme induction. Toxicol Lett 82–83:173–179

    Article  PubMed  Google Scholar 

  • Tsuji PA, Walle T (2007) Benzo[a]pyrene-induced cytochrome P450 1A and-DNA binding in cultured trout hepatocytes—inhibition by plant polyphenols. Chem Biol Interact 169:25–31

    Article  CAS  PubMed  Google Scholar 

  • Wang M-T, Honn KV, Nie D (2007) Cyclooxygenases, prostanoids, and tumor progression. Cancer Metastasis Rev 26:525–534

    Article  CAS  PubMed  Google Scholar 

  • WHO fact sheet 297 (2009)

  • Woynarowska BA, Woynarowski JM, Herzig MCS, Roberts K, Higdon AL, MacDonald JR (2000) Differential cytotoxicity and induction of apoptosis in tumor and normal cells by Hydroxymethylacylfulvene (HMAF). Biochem Pharmacol 59:1217–1226

    Article  CAS  PubMed  Google Scholar 

  • Woynarowski JM, Napier C, Koester SK, Chen SF, Troyer D, Chapman W, MacDonald JR (1997) Effects on DNA integrity and apoptosis induction by a novel antitumor sesquiterpene drug, 6-Hydroxymethylacylfulvene (HMAF, MGI 114). Biochem Pharmacol 54:1181–1193

    Article  CAS  PubMed  Google Scholar 

  • Yamada T, Iwamoto C, Yamagaki N, Yamanouchi T, Minoura K, Yamori T, Uehara Y, Andoh T, Uemura K, Numata A (2002) Leptosins M-N1, cytotoxic metabolites from a Leptosphaeria species separated from a marine alga. Structure determination and biological activites. Tetrahedron 58:479–487

    Article  CAS  Google Scholar 

  • Yanagihara M, Sasaki-Takahashi N, Sugahara T, Yamamoto S, Shinomi M, Yamashita T, Hayashida M, Yamanoha B, Numata A, Yamori T, Andoh T (2005) Leptosins isolated from marine fungus Leptosphaeria species inhibit DNA topoisomerases I and/or II and induce apoptosis by inactivation of Akt/protein kinase B. Cancer Sci 96:816–824

    Article  CAS  PubMed  Google Scholar 

  • Zhou G, Tsai CW, Liu JO (2003) Fumagalone, a reversible inhibitor of type 2 methionine aminopeptidase and angiogenesis. J Med Chem 46:3452–3454

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Financial support from the BMBF (Project No. 03F0415A) is gratefully acknowledged. I. E. M. gratefully acknowledges the University of Khartoum, Khartoum, Sudan for a study leave and generous financial support.

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Authors and Affiliations

  1. Institute for Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115, Bonn, Germany

    Hendrik Greve, Alexander Pontius, Stefan Kehraus, Harald Gross & Gabriele M. König

  2. Department of Botany, University of Khartoum, Khartoum, Sudan

    Ietidal E. Mohamed

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  1. Hendrik Greve
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  2. Ietidal E. Mohamed
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  3. Alexander Pontius
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  4. Stefan Kehraus
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  6. Gabriele M. König
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Correspondence to Gabriele M. König.

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Greve, H., Mohamed, I.E., Pontius, A. et al. Fungal metabolites: structural diversity as incentive for anticancer drug development. Phytochem Rev 9, 537–545 (2010). https://doi.org/10.1007/s11101-010-9198-5

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