Download PDF
Planta Med 2010; 76(11): 1075-1079
DOI: 10.1055/s-0030-1249961
Cancer Therapy
Reviews
© Georg Thieme Verlag KG Stuttgart · New York

Modulation of Apoptosis by Natural Products for Cancer Therapy

Simone Fulda1
  • 1Children's Hospital, Ulm University, Ulm, Germany
Further Information

Publication History

received January 13, 2010 revised March 26, 2010

accepted April 19, 2010

Publication Date:
19 May 2010 (online)

   Permissions and Reprints

Abstract

Natural products can exhibit many beneficial effects on human health. As far as cancer is concerned, naturally occurring compounds have been reported to prevent tumorigenesis and also to suppress the growth of established tumors. As cancer cells have evolved multiple mechanisms to resist the induction of programmed cell death (apoptosis), the modulation of apoptosis signaling pathways by natural compounds has been demonstrated to constitute a key event in these antitumor activities. This review presents some examples of how apoptosis pathways are targeted by selected naturally occurring agents and how these events can be exploited for cancer therapy.

Key words

natural products - apoptosis - cancer therapy

References

  • 1 Nobili S, Lippi D, Witort E, Donnini M, Bausi L, Mini E, Capaccioli S. Natural compounds for cancer treatment and prevention.  Pharmacol Res. 2009;  59 365-378
    CrossrefPubMedGoogle Scholar
  • 2 Lockshin R A, Zakeri Z. Cell death in health and disease.  J Cell Mol Med. 2007;  11 1214-1224
    CrossrefPubMedGoogle Scholar
  • 3 Fulda S. Tumor resistance to apoptosis.  Int J Cancer. 2009;  124 511-515
    CrossrefPubMedGoogle Scholar
  • 4 Hanahan D, Weinberg R A. The hallmarks of cancer.  Cell. 2000;  100 57-70
    CrossrefPubMedGoogle Scholar
  • 5 Degterev A, Boyce M, Yuan J. A decade of caspases.  Oncogene. 2003;  22 8543-8567
    CrossrefPubMedGoogle Scholar
  • 6 Fulda S, Debatin K M. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy.  Oncogene. 2006;  25 4798-4811
    CrossrefPubMedGoogle Scholar
  • 7 Ashkenazi A. Targeting the extrinsic apoptosis pathway in cancer.  Cytokine Growth Factor Rev. 2008;  19 325-331
    CrossrefPubMedGoogle Scholar
  • 8 Walczak H, Krammer P H. The CD95 (APO-1/Fas) and the TRAIL (APO-2 L) apoptosis systems.  Exp Cell Res. 2000;  256 58-66
    CrossrefPubMedGoogle Scholar
  • 9 Adams J M, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy.  Oncogene. 2007;  26 1324-1337
    CrossrefPubMedGoogle Scholar
  • 10 Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death.  Physiol Rev. 2007;  87 99-163
    CrossrefPubMedGoogle Scholar
  • 11 Saelens X, Festjens N, Vande Walle L, van Gurp M, van Loo G, Vandenabeele P. Toxic proteins released from mitochondria in cell death.  Oncogene. 2004;  23 2861-2874
    CrossrefPubMedGoogle Scholar
  • 12 LaCasse E C, Mahoney D J, Cheung H H, Plenchette S, Baird S, Korneluk R G. IAP-targeted therapies for cancer.  Oncogene. 2008;  27 6252-6275
    CrossrefPubMedGoogle Scholar
  • 13 Okada H, Mak T W. Pathways of apoptotic and non-apoptotic death in tumour cells.  Nat Rev Cancer. 2004;  4 592-603
    CrossrefPubMedGoogle Scholar
  • 14 Fulda S, Scaffidi C, Susin S A, Krammer P H, Kroemer G, Peter M E, Debatin K M. Activation of mitochondria and release of mitochondrial apoptogenic factors by betulinic acid.  J Biol Chem. 1998;  273 33942-33948
    CrossrefPubMedGoogle Scholar
  • 15 Fulda S, Friesen C, Los M, Scaffidi C, Mier W, Benedict M, Nunez G, Krammer P H, Peter M E, Debatin K M. Betulinic acid triggers CD95 (APO-1/Fas)- and p 53-independent apoptosis via activation of caspases in neuroectodermal tumors.  Cancer Res. 1997;  57 4956-4964
    PubMedGoogle Scholar
  • 16 Liby K T, Yore M M, Sporn M B. Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer.  Nat Rev Cancer. 2007;  7 357-369
    CrossrefPubMedGoogle Scholar
  • 17 Fulda S, Susin S A, Kroemer G, Debatin K M. Molecular ordering of apoptosis induced by anticancer drugs in neuroblastoma cells.  Cancer Res. 1998;  58 4453-4460
    PubMedGoogle Scholar
  • 18 Andre N, Carre M, Brasseur G, Pourroy B, Kovacic H, Briand C, Braguer D. Paclitaxel targets mitochondria upstream of caspase activation in intact human neuroblastoma cells.  FEBS Lett. 2002;  532 256-260
    CrossrefPubMedGoogle Scholar
  • 19 Zuco V, Supino R, Righetti S C, Cleris L, Marchesi E, Gambacorti-Passerini C, Formelli F. Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells.  Cancer Lett. 2002;  175 17-25
    CrossrefPubMedGoogle Scholar
  • 20 Salti G I, Kichina J V, Das Gupta T K, Uddin S, Bratescu L, Pezzuto J M, Mehta R G, Constantinou A I. Betulinic acid reduces ultraviolet-C-induced DNA breakage in congenital melanocytic naeval cells: evidence for a potential role as a chemopreventive agent.  Melanoma Res. 2001;  11 99-104
    CrossrefPubMedGoogle Scholar
  • 21 Meng R D, El-Deiry W S. p 53-independent upregulation of KILLER/DR5 TRAIL receptor expression by glucocorticoids and interferon-gamma.  Exp Cell Res. 2001;  262 154-169
    CrossrefPubMedGoogle Scholar
  • 22 Fulda S, Debatin K M. Betulinic acid induces apoptosis through a direct effect on mitochondria in neuroectodermal tumors.  Med Pediatr Oncol. 2000;  35 616-618
    CrossrefPubMedGoogle Scholar
  • 23 Wick W, Grimmel C, Wagenknecht B, Dichgans J, Weller M. Betulinic acid-induced apoptosis in glioma cells: a sequential requirement for new protein synthesis, formation of reactive oxygen species, and caspase processing.  J Pharmacol Exp Ther. 1999;  289 1306-1312
    PubMedGoogle Scholar
  • 24 Selzer E, Pimentel E, Wacheck V, Schlegel W, Pehamberger H, Jansen B, Kodym R. Effects of betulinic acid alone and in combination with irradiation in human melanoma cells.  J Invest Dermatol. 2000;  114 935-940
    CrossrefPubMedGoogle Scholar
  • 25 Gledhill J R, Montgomery M G, Leslie A G, Walker J E. Mechanism of inhibition of bovine F1-ATPase by resveratrol and related polyphenols.  Proc Natl Acad Sci USA. 2007;  104 13632-13637
    CrossrefPubMedGoogle Scholar
  • 26 Fulda S, Debatin K M. Sensitization for tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by the chemopreventive agent resveratrol.  Cancer Res. 2004;  64 337-346
    CrossrefPubMedGoogle Scholar
  • 27 Jazirehi A R, Bonavida B. Resveratrol modifies the expression of apoptotic regulatory proteins and sensitizes non-Hodgkin's lymphoma and multiple myeloma cell lines to paclitaxel-induced apoptosis.  Mol Cancer Ther. 2004;  3 71-84
    PubMedGoogle Scholar
  • 28 She Q-B, Huang C, Zhang Y, Dong Z. Involvement of c-jun NH(2)-terminal kinases in resveratrol-induced activation of p 53 and apoptosis.  Mol Carcinogen. 2002;  33 244-250
    CrossrefPubMedGoogle Scholar
  • 29 Kaneuchi M, Sasaki M, Tanaka Y, Yamamoto R, Sakuragi N, Dahiya R. Resveratrol suppresses growth of Ishikawa cells through down-regulation of EGF.  Int J Oncol. 2003;  23 1167-1172
    PubMedGoogle Scholar
  • 30 Pozo-Guisado E, Lorenzo-Benayas M J, Fernandez-Salguero P M. Resveratrol modulates the phosphoinositide 3-kinase pathway through an estrogen receptor alpha-dependent mechanism: relevance in cell proliferation.  Int J Cancer. 2004;  109 167-173
    CrossrefPubMedGoogle Scholar
  • 31 Jiang H, Shang X, Wu H, Gautam S C, Al-Holou S, Li C, Kuo J, Zhang L, Chopp M. Resveratrol downregulates PI3K/Akt/mTOR signaling pathways in human U251 glioma cells.  J Exp Ther Oncol. 2009;  8 25-33
    PubMedGoogle Scholar
  • 32 Shaw R J, Cantley L C. Ras, PI(3)K and mTOR signalling controls tumour cell growth.  Nature. 2006;  441 424-430
    CrossrefPubMedGoogle Scholar
  • 33 Biasutto L, Mattarei A, Marotta E, Bradaschia A, Sassi N, Garbisa S, Zoratti M, Paradisi C. Development of mitochondria-targeted derivatives of resveratrol.  Bioorg Med Chem Lett. 2008;  18 5594-5597
    CrossrefPubMedGoogle Scholar
  • 34 Constantinou C, Papas A, Constantinou A I. Vitamin E and cancer: an insight into the anticancer activities of vitamin E isomers and analogs.  Int J Cancer. 2008;  123 739-752
    CrossrefPubMedGoogle Scholar
  • 35 Dong L F, Low P, Dyason J C, Wang X F, Prochazka L, Witting P K, Freeman R, Swettenham E, Valis K, Liu J, Zobalova R, Turanek J, Spitz D R, Domann F E, Scheffler I E, Ralph S J, Neuzil J. Alpha-tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II.  Oncogene. 2008;  27 4324-4335
    CrossrefPubMedGoogle Scholar
  • 36 Dong L F, Swettenham E, Eliasson J, Wang X F, Gold M, Medunic Y, Stantic M, Low P, Prochazka L, Witting P K, Turanek J, Akporiaye E T, Ralph S J, Neuzil J. Vitamin E analogues inhibit angiogenesis by selective induction of apoptosis in proliferating endothelial cells: the role of oxidative stress.  Cancer Res. 2007;  67 11906-11913
    CrossrefPubMedGoogle Scholar
  • 37 Jia L, Yu W, Wang P, Sanders B G, Kline K. In vivo and in vitro studies of anticancer actions of alpha-TEA for human prostate cancer cells.  Prostate. 2008;  68 849-860
    CrossrefPubMedGoogle Scholar
  • 38 Hahn T, Szabo L, Gold M, Ramanathapuram L, Hurley L H, Akporiaye E T. Dietary administration of the proapoptotic vitamin E analogue alpha-tocopheryloxyacetic acid inhibits metastatic murine breast cancer.  Cancer Res. 2006;  66 9374-9378
    CrossrefPubMedGoogle Scholar
  • 39 Lawson K A, Anderson K, Simmons-Menchaca M, Atkinson J, Sun L, Sanders B G, Kline K. Comparison of vitamin E derivatives alpha-TEA and VES in reduction of mouse mammary tumor burden and metastasis.  Exp Biol Med (Maywood). 2004;  229 954-963
    PubMedGoogle Scholar
  • 40 Neuzil J, Weber T, Schroder A, Lu M, Ostermann G, Gellert N, Mayne G C, Olejnicka B, Negre-Salvayre A, Sticha M, Coffey R J, Weber C. Induction of cancer cell apoptosis by alpha-tocopheryl succinate: molecular pathways and structural requirements.  FASEB J. 2001;  15 403-415
    CrossrefPubMedGoogle Scholar
  • 41 Lynn A, Jones L. Gossypol and some other terpenoids, flavonoids, and phenols that affect quality of cottonseed protein.  J Am Oil Chem Soc. 1979;  56 727-730
    CrossrefPubMedGoogle Scholar
  • 42 Azmi A S, Mohammad R M. Non-peptidic small molecule inhibitors against Bcl-2 for cancer therapy.  J Cell Physiol. 2009;  218 13-21
    CrossrefPubMedGoogle Scholar
  • 43 Kitada S, Kress C L, Krajewska M, Jia L, Pellecchia M, Reed J C. Bcl-2 antagonist apogossypol (NSC736630) displays single-agent activity in Bcl-2-transgenic mice and has superior efficacy with less toxicity compared with gossypol (NSC19048).  Blood. 2008;  111 3211-3219
    CrossrefPubMedGoogle Scholar
  • 44 Liu G, Kelly W K, Wilding G, Leopold L, Brill K, Somer B. An open-label, multicenter, phase I/II study of single-agent AT-101 in men with castrate-resistant prostate cancer.  Clin Cancer Res. 2009;  15 3172-3176
    CrossrefPubMedGoogle Scholar
  • 45 Marchetti P, Zamzami N, Joseph B, Schraen-Maschke S, Mereau-Richard C, Costantini P, Metivier D, Susin S A, Kroemer G, Formstecher P. The novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid can trigger apoptosis through a mitochondrial pathway independent of the nucleus.  Cancer Res. 1999;  59 6257-6266
    PubMedGoogle Scholar
  • 46 Belzacq A S, El Hamel C, Vieira H L, Cohen I, Haouzi D, Metivier D, Marchetti P, Brenner C, Kroemer G. Adenine nucleotide translocator mediates the mitochondrial membrane permeabilization induced by lonidamine, arsenite and CD437.  Oncogene. 2001;  20 7579-7587
    CrossrefPubMedGoogle Scholar
  • 47 Notario B, Zamora M, Vinas O, Mampel T. All-trans-retinoic acid binds to and inhibits adenine nucleotide translocase and induces mitochondrial permeability transition.  Mol Pharmacol. 2003;  63 224-231
    CrossrefPubMedGoogle Scholar
  • 48 Trachootham D, Zhou Y, Zhang H, Demizu Y, Chen Z, Pelicano H, Chiao P J, Achanta G, Arlinghaus R B, Liu J, Huang P. Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by beta-phenylethyl isothiocyanate.  Cancer Cell. 2006;  10 241-252
    CrossrefPubMedGoogle Scholar
  • 49 Xiao D, Lew K L, Zeng Y, Xiao H, Marynowski S W, Dhir R, Singh S V. Phenethyl isothiocyanate-induced apoptosis in PC-3 human prostate cancer cells is mediated by reactive oxygen species-dependent disruption of the mitochondrial membrane potential.  Carcinogenesis. 2006;  27 2223-2234
    CrossrefPubMedGoogle Scholar
  • 50 Huang P, Feng L, Oldham E A, Keating M J, Plunkett W. Superoxide dismutase as a target for the selective killing of cancer cells.  Nature. 2000;  407 390-395
    CrossrefPubMedGoogle Scholar
  • 51 Juarez J C, Manuia M, Burnett M E, Betancourt O, Boivin B, Shaw D E, Tonks N K, Mazar A P, Donate F. Superoxide dismutase 1 (SOD1) is essential for H2O2-mediated oxidation and inactivation of phosphatases in growth factor signaling.  Proc Natl Acad Sci USA. 2008;  105 7147-7152
    CrossrefPubMedGoogle Scholar
  • 52 Kroemer G, Pouyssegur J. Tumor cell metabolism: cancer's Achilles' heel.  Cancer Cell. 2008;  13 472-482
    CrossrefPubMedGoogle Scholar
  • 53 Brahimi-Horn M C, Chiche J, Pouyssegur J. Hypoxia signalling controls metabolic demand.  Curr Opin Cell Biol. 2007;  19 223-229
    CrossrefPubMedGoogle Scholar
  • 54 Warburg O, Posener K, Negelein E. Über den Stoffwechsel der Tumoren.  Biochem Z. 1924;  152 319-344
    PubMedGoogle Scholar
  • 55 Abu-Hamad S, Zaid H, Israelson A, Nahon E, Shoshan-Barmatz V. Hexokinase-I protection against apoptotic cell death is mediated via interaction with the voltage-dependent anion channel-1: mapping the site of binding.  J Biol Chem. 2008;  283 13482-13490
    CrossrefPubMedGoogle Scholar
  • 56 Goldin N, Arzoine L, Heyfets A, Israelson A, Zaslavsky Z, Bravman T, Bronner V, Notcovich A, Shoshan-Barmatz V, Flescher E. Methyl jasmonate binds to and detaches mitochondria-bound hexokinase.  Oncogene. 2008;  27 4636-4643
    CrossrefPubMedGoogle Scholar
  • 57 Kitada S, Leone M, Sareth S, Zhai D, Reed J C, Pellecchia M. Discovery, characterization, and structure-activity relationships studies of proapoptotic polyphenols targeting B-cell lymphocyte/leukemia-2 proteins.  J Med Chem. 2003;  46 4259-4264
    CrossrefPubMedGoogle Scholar

Prof. Simone Fulda

University Children's Hospital

Eythstrasse 24

89075 Ulm

Germany

Phone: + 49 7 31 50 05 70 34

Fax: + 49 7 31 50 05 70 58

Email: simone.fulda@uniklinik-ulm.de

      >