Chemical-Biology of Natural Products from Medicinal Plants for Cancer Therapy



Secondary metabolites are produced by an organism for defense towards competitors, herbivores, and pathogens. They also act as signal compounds to attract animals for pollination and seed dispersal. Fortunately, many secondary metabolites from plants exhibit diverse pharmacological features. Exploitation of these beneficial effects is the primary goal of researchers working in the area of molecular pharmacology of natural products. Natural products are among the major players in pharmacology in general and in cancer therapy in particular. A considerable portion of antitumor agents currently used in the clinic are of natural origin (e.g. Vinca alkaloids, taxanes, podophyllotoxin, camptothecin derivatives, etc.). Among all chemical classes of natural products, we focus on alkaloids because of their high bioactivity and cytotoxicity. The major targets of alkaloids are DNA, RNA, biomembranes and membrane proteins, enzymes involved in DNA biosynthesis, DNA replication and repair, and protein biosynthesis and conformation. Because the response of tumor cells to cytotoxic agents is determined by multiple factors, and single mechanisms are not sufficient to account for a drug’s activity, genomewide approaches such as microarray technologies are attractive to decipher novel targets and determinants of chemosensitivity towards anticancer drugs. This has been exemplified in this chapter for selected compounds. Although the potential of natural products is increasingly recognized in oncology, it has been estimated that only 15% of all plant species have been investigated exhaustively for potential medical applications. In our opinion, the full potential of natural products will be developed in the years to come.


Secondary Metabolite Medicinal Plant Natural Product Vinca Alkaloid Natural Product Research 
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.


  1. 1.
    Roth I, Lindorf H. South American medicinal plants. Berlin, Germany: Springer; 2002.Google Scholar
  2. 2.
    Schmeller T, Latz-Brüning B, Wink M. Biochemical activities of berberine, palmatine and sanguinarine mediating chemical defence against microorganisms and herbivores. Phytochemistry 1997;44:257–66.CrossRefGoogle Scholar
  3. 3.
    Wink M. Allelochemical properties and the raison d'être of alkaloids. In: Cordell G, editor. The alkaloids. New York: Academic Press; 1993. Vol. 43, pp. 1–118.Google Scholar
  4. 4.
    Wink M. Evolution of secondary metabolites from an ecological and molecular phylogenetic perspective. Phytochemistry 2003;64:3–19.PubMedCrossRefGoogle Scholar
  5. 5.
    Wink M. Plant secondary metabolism: Diversity, function and its evolution. Nat Prod Commun. 2008;3:1205–16.Google Scholar
  6. 6.
    Wink M. Ecological roles of alkaloids. In: Fattorusso E, Taglialatela-Scafati E, editors. Modern alkaloids: structure, isolation, synthesis, and biology. Weinheim: Wiley-VCH; 2008. pp. 3–24.Google Scholar
  7. 7.
    Wink, M. Evolutionary advantage and molecular modes of action of multi-component mixtures in phytomedicine. Curr Drug Metab. 2008;9:996–1009.Google Scholar
  8. 8.
    Mothes K. Physiology of alkaloids. Annu Rev Plant Physiol. 1955;6:393–493.CrossRefGoogle Scholar
  9. 9.
    Wink M. Plant breeding: Importance of plant secondary metabolites for protection against pathogens and herbivores. Theor Appl Genet. 1988;75;225–33.Google Scholar
  10. 10.
    Wink, M. Biochemistry of plant secondary metabolism. In: Wink M, editor. Annual plant review. Sheffield: Academic Press and CRC Press; 1999; Vol. 2, p. 1.Google Scholar
  11. 11.
    Wink M. Interference of alkaloids with neuroreceptors and ion channels. In: Atta-Ur-Rahman editor. Bioactive natural products. Amsterdam: Elsevier; 2000; Vol. 11, pp. 3–129.Google Scholar
  12. 12.
    Moed L, Shwayder TA, Chang MW. Cantharidin revisited: a blistering defense of an ancient medicine. Arch Dermatol. 2001;137:1357–60.Google Scholar
  13. 13.
    Silverberg N. Pediatric molluscum contagiosum: optimal treatment strategies. Paediatr Drugs 2003;5:505–12.Google Scholar
  14. 14.
    Smolinski KN, Yan AC. How and when to treat molluscum contagiosum and warts in children. Pediatr Ann. 2005;34:211–21.Google Scholar
  15. 15.
    Karras DJ, Farrell SE, Harrigan RA, Henretig FM, Gealt L. Poisoning from “Spanish fly” (cantharidin). Am J Emerg Med. 1996;14:478–83.CrossRefGoogle Scholar
  16. 16.
    Efferth T, Rauh R, Kahl S, Tomicic M, Böchzelt H, Tome ME, Briehl MM, Bauer R, Kaina B. Molecular modes of action of cantharidin in tumor cells. Biochem Pharmacol. 2005;69:811–18.CrossRefGoogle Scholar
  17. 17.
    Swingle M, Ni L, Honkanen RE. Small-molecule inhibitors of ser/thr protein phosphatases: specificity, use and common forms of abuse. Methods Mol Biol. 2007;365:23–38.PubMedGoogle Scholar
  18. 18.
    Rauh R, Kahl S, Boechzelt H, Bauer R, Kaina B, Efferth T. Molecular biology of cantharidin in cancer cells. Chin Med. 2007;2:8.PubMedCrossRefGoogle Scholar
  19. 19.
    van Wyk BE, Wink M. Medicinal plants of the world. Pretoria: Briza; 2004.Google Scholar
  20. 20.
    Wink M, van Wyk BE. Mind-altering and poisonous plants of the world. Pretoria: Briza; 2008.Google Scholar
  21. 21.
    Newman DJ, Cragg GM. Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007;70:461–77.CrossRefGoogle Scholar
  22. 22.
    Wink M. Importance of plant secondary metabolites for protection against insects and microbial infections. In: Carpinella C, Rai M, editors. Naturally occurring bioactive compounds: A new and safe alternative for control of pests and diseases. 2007;251–68.Google Scholar
  23. 23.
    Wink M. Bioprospecting: the search for bioactive lead structures from Nature. In: Kayser O, Quax W, editors. Medical plant biotechnology. From basic research to industrial applications. Weinheim: Wiley-VCH; 2007;1:97–116.Google Scholar
  24. 24.
    Wink M. Wie funktionieren Phytopharmaka? Z Phytother. 2005;26:262–70.CrossRefGoogle Scholar
  25. 25.
    Reichenbach H, Höfle G. Discovery and development of the epothilones: a novel class of antineoplastic drugs. Drugs R D. 2008;9:1–10.PubMedCrossRefGoogle Scholar
  26. 26.
    Müller H, Brackhagen O, Brunne R, Henkel T, Reichel F. Natural products in drug discovery. Ernst Schering Res Found Workshop 2000;32:205–16.Google Scholar
  27. 27.
    Lee ML, Schneider GJ. Scaffold architecture and pharmacophoric properties of natural products and trade drugs: application in the design of natural product-based combinatorial libraries. J Comb Chem. 2001;32:284–9.Google Scholar
  28. 28.
    Konkimalla VB, Efferth T. Anti-cancer natural product library from traditional chinese medicine. Comb Chem High Throughput Screen 2008;11:7–15.PubMedCrossRefGoogle Scholar
  29. 29.
    Wink M. Molecular modes of action of cytotoxic alkaloids – from DNA intercalation, spindle poisoning, topoisomerase inhibition to apoptosis and multiple drug resistance. In: Cordell G, editors. The alkaloids. New York: Elsevier; 2007. Vol. 64, pp. 1–48.Google Scholar
  30. 30.
    Roberts MF, Wink M. Alkaloids: biochemistry, ecology, and medical applications. New York, NY: Plenum Press; 1998.Google Scholar
  31. 31.
    Wink M, Schmeller T, Latz-Brüning B. Modes of action of allelochemical alkaloids: interaction with neuroreceptors, DNA, and other molecular targets. J Chem Ecol. 1998;24:1881–1937.CrossRefGoogle Scholar
  32. 32.
    Efferth T, Grassmann R. Impact of viral oncogenesis in responses to anti-cancer drugs and irradiation. Crit Rev Oncogen. 2000;11:165–87.Google Scholar
  33. 33.
    Volm M, Koomägi R, Mattern J, Efferth T. Protein expression profiles indicative for drug resistance of non-small cell lung cancer. Br J Cancer 2002;87:251–7.CrossRefGoogle Scholar
  34. 34.
    Volm M, Koomägi R, Mattern J, Efferth T. Expression profile of genes in non-small cell lung carcinomas from long-term surviving patients. Clin Cancer Res. 2002;8:1843–8.Google Scholar
  35. 35.
    Volm M, Koomägi R, Efferth T. Prediction of drug sensitivity and resistance of cancer by protein expression profiling. Cancer Genomics Proteomics 2004;1:157–66.Google Scholar
  36. 36.
    Efferth T. Mechanistic perspectives for 1,2,4-trioxanes in anti-cancer therapy. Drug Resist Updat. 2005;8:85–97.PubMedCrossRefGoogle Scholar
  37. 37.
    Efferth T. Molecular pharmacology and pharmacogenomics of artemisinin and its derivatives in cancer cells. Curr Drug Targets 2006;7:407–21.Google Scholar
  38. 38.
    Efferth T, Li PC, Konkimalla VS, Kaina B. From traditional Chinese medicine to rational cancer therapy. Trends Mol Med. 2007;13:353–61.CrossRefGoogle Scholar
  39. 39.
    Efferth T, Fu YJ, Zu YG, Schwarz G, Konkimalla VS, Wink M. Molecular target-guided tumor therapy with natural products derived from traditional Chinese medicine. Curr Med Chem. 2007;14:2024–32.Google Scholar
  40. 40.
    Efferth T. Willmar Schwabe Award 2006: antiplasmodial and antitumor activity of artemisinin – from bench to bedside. Planta Med. 2007;73:299–309.PubMedCrossRefGoogle Scholar
  41. 41.
    Wink M. In: Cordell GA, editor. The alkaloids: chemistry and biology. San Diego, CA: Academic Press; 1993. Vol. 43, p. 1.Google Scholar
  42. 42.
    Wink M: Molecular modes of action of cytotoxic alkaloids: from DNA intercolation, spindle poisoning, to poisonerase inhibition to apoptosis and multiple drug resistance. Alkaloids Chem Biol. 2007;64:1–47.Google Scholar
  43. 43.
    Wink M, Schimmer O. Molecular modes of action of defensive secondary metabolites. In: Wink M, edition. Functions and biotechnology of plant secondary metabolites. Annual Plant Reviews. Wiley-Blackwelll; 2010. Vol. 39, pp. 21–161.Google Scholar
  44. 44.
    Christmann M, Tomicic MT, Roos WP, Kaina B. Mechanisms of human DNA repair: an update. Toxicology 2003;193:31–4.CrossRefGoogle Scholar
  45. 45.
    Schwarzl SM, Smith JC, Kaina B, Efferth T. Molecular modeling of O6-methylguanine-DNA methyltransferase mutant proteins encoded by single nucleotide polymorphisms. Int J Mol Med. 2005;16:553–7.Google Scholar
  46. 46.
    Konkimalla VS, Wang G, Kaina B, Efferth T. Microarray-based expression of DNA repair genes does not correlate with growth inhibition of cancer cells by natural products derived from traditional Chinese medicine. Cancer Genomics Proteomics 2008;5:79–84.PubMedGoogle Scholar
  47. 47.
    Li PC, Lam E, Roos WP, Zdzienicka MZ, Kaina B, Efferth T. Artesunate derived from traditional Chinese medicine induces DNA damage and repair. Cancer Res. 2008;68:4347–51.Google Scholar
  48. 48.
    Mazzini S, Bellucci MC, Mondelli R. Mode of binding of the cytotoxic alkaloid berberine with the double helix oligonucleotide d(AAGAATTCTT)(2). Bioorg Med Chem. 2003;11:505–14.CrossRefGoogle Scholar
  49. 49.
    Garbett NC, Graves DE. Extending nature's leads: the anticancer agent ellipticine. Curr Med Chem Anticancer Agents 2004;4:149–72.CrossRefGoogle Scholar
  50. 50.
    Hofmann GA, Mattern MR. Topoisomerase II in multiple drug resistance. Cytotechnology 1993;12:137–54.CrossRefGoogle Scholar
  51. 51.
    Denny WA. Dual topoisomerase I/II poisons as anticancer drugs. Expert Opin Investig. Drugs. 1997;6:1845–51.CrossRefGoogle Scholar
  52. 52.
    Bailly C. Topoisomerase I poisons and suppressors as anticancer drugs. Curr Med Chem. 2000;7:39–58.PubMedCrossRefGoogle Scholar
  53. 53.
    Dassonneville L, Bonjean K, De Pauw-Gillet MC, Colson P, Houssier C, Quetin-Leclercq J, Angenot L, Bailly C. Stimulation of topoisomerase II-mediated DNA cleavage by three DNA-intercalating plant alkaloids: cryptolepine, matadine, and serpentine. Biochemistry 1999;38:7719–26.CrossRefGoogle Scholar
  54. 54.
    Neidle S, Parkinson GN. Quadruplex DNA crystal structures and drug design. Biochimie 2008;90:1184–96.CrossRefGoogle Scholar
  55. 55.
    Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL, Shay JW. Specific association of human telomerase activity with immortal cells and cancer. Science 1994;266:2011–15.CrossRefGoogle Scholar
  56. 56.
    Read MA, Wood AA, Harrison JR, Gowan SM, Kelland LR, Dosanjh HS, Neidle S. Molecular modeling studies on G-quadruplex complexes of telomerase inhibitors: structure-activity relationships. J Med Chem. 1999;42:4538–46.CrossRefGoogle Scholar
  57. 57.
    Demeunynck M, Charmantray F, Martelli A. Interest of acridine derivatives in the anticancer chemotherapy. Curr Pharm Des. 2001;7:1703–24.Google Scholar
  58. 58.
    Sato N, Mizumoto K, Kusumoto M, Niiyama H, Maehara N, Ogawa T, Tanaka M. 9-Hydroxyellipticine inhibits telomerase activity in human pancreatic cancer cells. FEBS Lett. 1998;441:318–21.Google Scholar
  59. 59.
    Guittat L, Alberti P, Rosu F, Van Miert S, Thetiot E, Pieters L, Gabelica V, De Pauw E, Ottaviani A, Riou JF, Mergny JL. Interactions of cryptolepine and neocryptolepine with unusual DNA structures. Biochimie 2003;85:535–47.CrossRefGoogle Scholar
  60. 60.
    Caprio V, Guyen B, Opoku-Boahen Y, Mann J, Gowan SM, Kelland LM, Read MA, Neidle S. A novel inhibitor of human telomerase derived from 10H-indolo[3,2-b]quinoline. Bioorg Med Chem Lett. 2000;10:2063–6.CrossRefGoogle Scholar
  61. 61.
    Naasani I, Seimiya H, Yamori T, Tsuruo T. FJ5002: a potent telomerase inhibitor identified by exploiting the disease-oriented screening program with COMPARE analysis. Cancer Res. 1999;59:4004–11.Google Scholar
  62. 62.
    Warabi K, Matsunaga S, van Soest RW, Fusetani N. Dictyodendrins A-E, the first telomerase-inhibitory marine natural products from the sponge Dictyodendrilla verongiformis. J Org Chem. 2003;68:2765–70.CrossRefGoogle Scholar
  63. 63.
    Zahler AM, Williamson JR, Cech TR, Prescott DM. Inhibition of telomerase by G-quartet DNA structures. Nature 1991;350:718–20.CrossRefGoogle Scholar
  64. 64.
    Zhou J, Giannakakou P. Targeting microtubules for cancer chemotherapy. Curr Med Chem Anticancer Agents 2005;5:65–71.PubMedCrossRefGoogle Scholar
  65. 65.
    Abal M, Andreu JM, Barasoain I. Taxanes: microtubule and centrosome targets, and cell cycle dependent mechanisms of action. Curr Cancer Drug Targets 2003;3:193–203.PubMedCrossRefGoogle Scholar
  66. 66.
    Pellegrini F, Budman DR. Review: tubulin function, action of antitubulin drugs, and new drug development. Cancer Invest 2005;23(3):264–73.CrossRefGoogle Scholar
  67. 67.
    Schulze-Bergkamen H, Krammer PH. Apoptosis in cancer – implications for therapy. Semin Oncol. 2004;31:90–119.PubMedCrossRefGoogle Scholar
  68. 68.
    Rosenkranz V, Wink M. Alkaloids induce programmed cell death in bloodstream forms of trypanosomes (Trypanosoma b. brucei). Molecules 2008;13:2462–73.CrossRefGoogle Scholar
  69. 69.
    Rosenkranz V, Wink M. Induction of apoptosis by alkaloids in human promyelotic HL-60 cells. Z. Naturforsch, C: J Biosci. 2007;62c:458–66.Google Scholar
  70. 70.
    Gillet JP, Efferth T, Remacle J. Chemotherapy-induced resistance by ATP-binding cassette transporter genes. Biochim Biophys Acta. 2007;1775:237–62.Google Scholar
  71. 71.
    Wang FP, Wang L, Yang JS, Nomura M, Miyamoto K. Reversal of P-glycoprotein-dependent resistance to vinblastine by newly synthesized bisbenzylisoquinoline alkaloids in mouse leukemia P388 cells. Biol Pharm Bull. 2005;28:1979–82.Google Scholar
  72. 72.
    Arora A, Seth K, Shukla Y. Reversal of P-glycoprotein-mediated multidrug resistance by diallyl sulfide in K562 leukemic cells and in mouse liver. Carcinogenesis 2004;25:941–9.CrossRefGoogle Scholar
  73. 73.
    Arora A, Seth K, Kalra N, Shukla Y. Modulation of P-glycoprotein-mediated multidrug resistance in K562 leukemic cells by indole-3-carbinol. Toxicol Appl Pharmacol. 2005;202:237–43.CrossRefGoogle Scholar
  74. 74.
    Efferth T, Olbrich A, Bauer R. mRNA expression profiles for the response of human tumor cell lines to the antimalarial drugs artesunate, arteether, and artemether. Biochem Pharmacol. 2002;64:617–23.CrossRefGoogle Scholar
  75. 75.
    Efferth T, Sauerbrey A, Halatsch ME, Ross DD, Gebhart E. Molecular modes of action of cephalotaxine and homoharringtonine from the coniferous tree Cephalotaxus hainanensis in human tumor cell lines. Naunyn Schmiedebergs Arch Pharmacol. 2003;367:56–67.PubMedCrossRefGoogle Scholar
  76. 76.
    Efferth T, Sauerbrey A, Olbrich A, Gebhart E, Rauch P, Weber HO, Hengstler JG, Halatsch ME, Volm M, Tew KD, Ross DD, Funk JO. Molecular modes of action of artesunate in tumor cell lines. Mol Pharmacol. 2003;64:382–94.CrossRefGoogle Scholar
  77. 77.
    Efferth T, Oesch F. Oxidative stress response of tumor cells: microarray-based comparison between artemisinins and anthracyclines. Biochem Pharmacol. 2004;68:3–10.PubMedCrossRefGoogle Scholar
  78. 78.
    Efferth T. Microarray-based prediction of cytotoxicity of tumor cells to cantharidin. Oncol Rep. 2005;13:459–63.Google Scholar
  79. 79.
    Efferth T, Chen Z, Kaina B, Wang G. Molecular determinants of response of tumor cells to berberine. Cancer Genomics Proteomics 2005;2:115–25.Google Scholar
  80. 80.
    Anfosso L, Efferth T, Albini A, Pfeffer U. Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins. Pharmacogenomics J. 2006;6:269–78.CrossRefGoogle Scholar
  81. 81.
    Efferth T, Miyachi H, Bartsch H. Pharmacogenomics of a traditional Japanese herbal medicine (Kampo) for cancer therapy. Cancer Genomics Proteomics 2007;4:81–91.PubMedGoogle Scholar
  82. 82.
    Efferth T, Kahl S, Paulus K, Adams M, Rauh R, Boechzelt H, Hao X, Kaina B, Bauer R. Phytochemistry and pharmacogenomics of natural products derived from traditional Chinese medicine and Chinese materia medica with activity against tumor cells. Mol Cancer Ther. 2008;7:152–61.CrossRefGoogle Scholar
  83. 83.
    Konkimalla VB, Blunder M, Korn B, Soomro SA, Jansen H, Chang W, Posner GH, Bauer R, Efferth T. Effect of artemisinins and other endoperoxides on nitric oxide-related signaling pathway in RAW 264.7 mouse macrophage cells. Nitric Oxide 2008;19:184–91.Google Scholar
  84. 84.
    Alley MC, Scudiero DA, Monks A, Hursey ML, Czerwinski MJ, Fine DL, Abbott BJ, Mayo JG, Shoemaker RH, Boyd MR. Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res. 1988; 48:589–01.Google Scholar
  85. 85.
    Rubinstein LV, Shoemaker RH, Paull KD, Simon RM, Tosini S, Skehan P, Scudiero DA, Monks A, Boyd MR. Comparison of in vitro anticancer-drug-screening data generated with a tetrazolium assay versus a protein assay against a diverse panel of human tumor cell lines. J Natl Cancer Inst. 1990;82:1113–18.CrossRefGoogle Scholar
  86. 86.
    Wosikowski K, Schuurhuis D, Johnson K, Paull KD, Myers TG, Weinstein JN, Bates SE. Identification of epidermal growth factor receptor and c-erbB2 pathway inhibitors by correlation with gene expression patterns. J Natl Cancer Inst. 1997;89:1505–15.CrossRefGoogle Scholar
  87. 87.
    Scherf U, Ross DT, Waltham M, Smith LH, Lee JK, Tanabe L, Kohn KW, Reinhold WC, Myers TG, Andrews DT, Scudiero DA, Eisen MB, Sausville EA, Pommier Y, Botstein D, Brown PO, Weinstein JN. A gene expression database for the molecular pharmacology of cancer. Nat Genet. 2000;24:236–44.CrossRefGoogle Scholar
  88. 88.
    Staunton JE, Slonim DK, Coller HA, Tamayo P, Angelo MJ, Park J, Scherf U, Lee JK, Reinhold WO, Weinstein JN, Mesirov JP, Lander ES, Golub TR. Chemosensitivity prediction by transcriptional profiling. Proc Natl Acad Sci USA 2001;98:10787–92.CrossRefGoogle Scholar
  89. 89.
    Russo D, Michelutti A, Melli C, Damiani D, Michieli MG, Candoni A, Zhou DC, Marie JP, Zittoun R, Baccarani M. MDR-related P170-glycoprotein modulates cytotoxic activity of homoharringtonine. Leukemia 1995;9:513–16.Google Scholar
  90. 90.
    Efferth T, Davey M, Olbrich A, Rücker G, Gebhart E, Davey R. Activity of drugs from traditional Chinese medicine toward sensitive and MDR1- or MRP1-overexpressing multidrug-resistant human CCRF-CEM leukemia cells. Blood Cells Mol Dis. 2002;28:160–8.Google Scholar
  91. 91.
    Efferth T, Sauerbrey A, Halatsch ME, Ross DD, Gebhart E. Molecular modes of action of cephalotaxine and homoharringtonine from the coniferous tree Cephalotaxus hainanensis in human tumor cell lines. Naunyn Schmiedebergs Arch Pharmacol. 2003;367:56–67.PubMedCrossRefGoogle Scholar
  92. 92.
    Cragg GM, Newman DJ. Plants as a source of anti-cancer agents. J Ethnopharmacol. 2005;100:72–9.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Pharmaceutical Biology, Institute of Pharmacy and BiochemistryUniversity of MainzMainzGermany
  2. 2.Department of Biology, Institute of Pharmacy and Molecular BiotechnologyUniversity of HeidelbergHeidelbergGermany

Personalised recommendations