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Myrtucommulone from Myrtus communis induces apoptosis in cancer cells via the mitochondrial pathway involving caspase-9

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Abstract

Myrtucommulone (MC) is a unique, nonprenylated acylphloroglucinol contained in the leaves of myrtle (Myrtus communis). Here, we addressed the potential of MC to induce apoptosis of cancer cells. MC potently induced cell death of different cancer cell lines (EC50 3–8 μM) with characteristics of apoptosis, visualized by the activation of caspase-3, -8 and -9, cleavage of poly(ADP-ribose)polymerase (PARP), release of nucleosomes into the cytosol, and DNA fragmentation. MC was much less cytotoxic for non-transformed human peripheral blood mononuclear cells (PBMC) or foreskin fibroblasts (EC50 cell death = 20–50 μM), and MC up to 30 μM hardly caused processing of PARP, caspase-3, -8 and -9 in human PBMC. MC-induced apoptosis was mediated by the intrinsic rather than the extrinsic death pathway. Thus, MC caused loss of the mitochondrial membrane potential in MM6 cells and evoked release of cytochrome c from mitochondria. Interestingly, Jurkat cells deficient in caspase-9 were resistant to MC-induced cell death and no processing of PARP or caspase-8 was evident. In cell lines deficient in either CD95 (Fas, APO-1) signalling, FADD or caspase-8, MC was still able to potently induce cell death and PARP cleavage. Conclusively, MC induces apoptosis in cancer cell lines, with marginal cytotoxicity for non-transformed cells, via the mitochondrial cytochrome c/Apaf-1/caspase-9 pathway.

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Abbreviations

CHX:

Cycloheximide

FADD:

Fas-associated death domain

IBP-C:

Isobutyrophenone core

5-LO:

5-Lipoxygenase

MC:

Myrtucommulone

ΔΨ m :

Mitochondrial membrane potential

MM6:

Mono Mac 6

PARP:

Poly(ADP-ribose)polymerase

PBMC:

Peripheral blood mononuclear cells

S-MC:

Semi-myrtucommulone

TNF:

Tumour necrosis factor

References

  1. Danial NN, Korsmeyer SJ (2004) Cell death: critical control points. Cell 116:205–219

    Article  PubMed  CAS  Google Scholar 

  2. Thompson CB (1995) Apoptosis in the pathogenesis and treatment of disease. Science 267:1456–1462

    Article  PubMed  CAS  Google Scholar 

  3. Fesik SW (2005) Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer 5:876–885

    Article  PubMed  CAS  Google Scholar 

  4. Nicholson DW (2000) From bench to clinic with apoptosis-based therapeutic agents. Nature 407:810–816

    Article  PubMed  CAS  Google Scholar 

  5. Tan G, Gyllenhaal C, Soejarto DD (2006) Biodiversity as a source of anticancer drugs. Curr Drug Targets 7:265–277

    Article  PubMed  CAS  Google Scholar 

  6. Nagata S (1997) Apoptosis by death factor. Cell 88:355–365

    Article  PubMed  CAS  Google Scholar 

  7. Green DR, Kroemer G (2004) The pathophysiology of mitochondrial cell death. Science 305:626–629

    Article  PubMed  CAS  Google Scholar 

  8. Thornberry NA, Lazebnik Y (1998) Caspases: enemies within. Science 281:1312–1316

    Article  PubMed  CAS  Google Scholar 

  9. Galluzzi L, Larochette N, Zamzami N et al (2006) Mitochondria as therapeutic targets for cancer chemotherapy. Oncogene 25:4812–4830

    Article  PubMed  CAS  Google Scholar 

  10. Al-Saimary IE, Bakr SS, Jaffar T et al (2002) Effects of some plant extracts and antibiotics on Pseudomonas aeruginosa isolated from various burn cases. Saudi Med J 23:802–805

    PubMed  Google Scholar 

  11. Elfellah MS, Akhter MH, Khan MT (1984) Anti-hyperglycaemic effect of an extract of Myrtus communis in streptozotocin-induced diabetes in mice. J Ethnopharmacol 11:275–281

    Article  PubMed  CAS  Google Scholar 

  12. Onal S, Timur S, Okutucu B et al (2005) Inhibition of alpha-glucosidase by aqueous extracts of some potent antidiabetic medicinal herbs. Prep Biochem Biotechnol 35:29–36

    Article  PubMed  CAS  Google Scholar 

  13. Levesque H, Lafont O (2000) Aspirin throughout the ages: a historical review. Rev Med Interne 21(Suppl 1):8s–17s

    Article  PubMed  Google Scholar 

  14. Rosa A, Deiana M, Casu V et al (2003) Antioxidant activity of oligomeric acylphloroglucinols from Myrtus communis L. Free Radic Res 37:1013–1019

    Article  PubMed  CAS  Google Scholar 

  15. Appendino G, Bianchi F, Minassi A et al (2002) Oligomeric acylphloroglucinols from myrtle (Myrtus communis). J Nat Prod 65:334–338

    Article  PubMed  CAS  Google Scholar 

  16. Feisst C, Franke L, Appendino G et al (2005) Identification of molecular targets of the oligomeric nonprenylated acylphloroglucinols from Myrtus communis and their implication as anti-inflammatory compounds. J Pharmacol Exp Ther 315:389–396

    Article  PubMed  CAS  Google Scholar 

  17. Samraj AK, Sohn D, Schulze-Osthoff K et al (2007) Loss of caspase-9 reveals its essential role for caspase-2 activation and mitochondrial membrane depolarization. Mol Biol Cell 18:84–93

    Article  PubMed  CAS  Google Scholar 

  18. Cinatl J, Herneiz P, Rabenau H et al (1994) Induction of myogenic differentiation in a human rhabdomyosarcoma cell line by phenylacetate. Cancer Lett 78:41–48

    Article  PubMed  CAS  Google Scholar 

  19. Kotchetkov R, Driever PH, Cinatl J et al (2005) Increased malignant behavior in neuroblastoma cells with acquired multi-drug resistance does not depend on P-gp expression. Int J Oncol 27:1029–1037

    PubMed  CAS  Google Scholar 

  20. Michaelis M, Kohler N, Reinisch A et al (2004) Increased human cytomegalovirus replication in fibroblasts after treatment with therapeutical plasma concentrations of valproic acid. Biochem Pharmacol 68:531–538

    Article  PubMed  CAS  Google Scholar 

  21. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63

    Article  PubMed  CAS  Google Scholar 

  22. Michaelis M, Suhan T, Cinatl J et al (2004) Valproic acid and interferon-alpha synergistically inhibit neuroblastoma cell growth in vitro and in vivo. Int J Oncol 25:1795–1799

    PubMed  CAS  Google Scholar 

  23. Nicoletti I, Migliorati G, Pagliacci MC et al (1991) A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods 139: 271–279

    Article  PubMed  CAS  Google Scholar 

  24. Zwelling LA, Altschuler E, Cherif A et al (1991) N-(5,5-diacetoxypentyl)doxorubicin: a novel anthracycline producing DNA interstrand cross-linking and rapid endonucleolytic cleavage in human leukemia cells. Cancer Res 51:6704–6707

    PubMed  CAS  Google Scholar 

  25. Lazebnik YA, Kaufmann SH, Desnoyers S et al (1994) Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE. Nature 371:346–347

    Article  PubMed  CAS  Google Scholar 

  26. Werz O, Steinhilber D (2006) Therapeutic options for 5-lipoxygenase inhibitors. Pharmacol Ther 112:701–718

    Article  PubMed  CAS  Google Scholar 

  27. Budihardjo I, Oliver H, Lutter M et al (1999) Biochemical pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol 15:269–290

    Article  PubMed  CAS  Google Scholar 

  28. Peterson EJ, Latinis KM, Koretzky GA (1998) Molecular characterization of a CD95 signaling mutant. Arthritis Rheum 41:1047–1053

    Article  PubMed  CAS  Google Scholar 

  29. Ghaemmaghami M, Jett JR (1998) New agents in the treatment of small cell lung cancer. Chest 113:86S–91S

    PubMed  CAS  Google Scholar 

  30. Cragg GM, Newman DJ (2005) Plants as a source of anti-cancer agents. J Ethnopharmacol 100:72–79

    Article  PubMed  CAS  Google Scholar 

  31. Brown JM, Attardi LD (2005) The role of apoptosis in cancer development and treatment response. Nat Rev Cancer 5:231–237

    Article  PubMed  CAS  Google Scholar 

  32. Loo DT, Rillema JR (1998) Measurement of cell death. Methods Cell Biol 57:251–264

    Article  PubMed  CAS  Google Scholar 

  33. Luo X, Budihardjo I, Zou H et al (1998) Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94:481–490

    Article  PubMed  CAS  Google Scholar 

  34. Maccarrone M, Taccone-Gallucci M and Finazzi-Agro A (2003) 5-Lipoxygenase-mediated mitochondrial damage and apoptosis of mononuclear cells in ESRD patients. Kidney Int Suppl:S33–S36

  35. Ding XZ, Iversen P, Cluck MW et al (1999) Lipoxygenase inhibitors abolish proliferation of human pancreatic cancer cells. Biochem Biophys Res Commun 261:218–223

    Article  PubMed  CAS  Google Scholar 

  36. Ghosh J, Myers CE (1997) Arachidonic acid stimulates prostate cancer cell growth: critical role of 5-lipoxygenase. Biochem Biophys Res Commun 235:418–423

    Article  PubMed  CAS  Google Scholar 

  37. Romano M, Catalano A, Nutini M et al (2001) 5-lipoxygenase regulates malignant mesothelial cell survival: involvement of vascular endothelial growth factor. FASEB J 15:2326–2336

    Article  PubMed  CAS  Google Scholar 

  38. Benchimol S (2001) p53-dependent pathways of apoptosis. Cell Death Differ 8:1049–1051

    Article  PubMed  CAS  Google Scholar 

  39. Lowe SW, Ruley HE, Jacks T et al (1993) p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74:957–967

    Article  PubMed  CAS  Google Scholar 

  40. Brown JM, Wouters BG (1999) Apoptosis, p53, and tumor cell sensitivity to anticancer agents. Cancer Res 59:1391–1399

    PubMed  CAS  Google Scholar 

  41. Wolf D, Rotter V (1985) Major deletions in the gene encoding the p53 tumor antigen cause lack of p53 expression in HL-60 cells. Proc Natl Acad Sci USA 82:790–794

    Article  PubMed  CAS  Google Scholar 

  42. Rokhlin OW, Bishop GA, Hostager BS et al (1997) Fas-mediated apoptosis in human prostatic carcinoma cell lines. Cancer Res 57:1758–1768

    PubMed  CAS  Google Scholar 

  43. Strasser A (2005) The role of BH3-only proteins in the immune system. Nat Rev Immunol 5:189–200

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Institute of Pharmaceutical Chemistry, University of Frankfurt, Max-von-Laue Str. 9, 60438, Frankfurt am Main, Germany

    Irina Tretiakova

  2. Department of Pharmaceutical Analytics, Pharmaceutical Institute, University of Tuebingen, Auf der Morgenstelle 8, 72076, Tuebingen, Germany

    Dagmar Blaesius & Oliver Werz

  3. COSMESE, Viale San Ignazio 13, Cagliari, 09123, Italy

    Lucia Maxia

  4. Department of Internal Medicine I, University of Tuebingen, Otfried-Mueller-Str. 10, 72076, Tuebingen, Germany

    Sebastian Wesselborg

  5. Institute of Molecular Medicine, Heinrich-Heine-University, Universitätsstr. 1, 40225, Duesseldorf, Germany

    Klaus Schulze-Osthoff

  6. Institute of Medical Virology, University Hospital Frankfurt, Paul Ehrlich-Str. 40, 60596, Frankfurt am Main, Germany

    Jindrich Cinatl Jr & Martin Michaelis

Authors
  1. Irina Tretiakova
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  2. Dagmar Blaesius
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  3. Lucia Maxia
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  4. Sebastian Wesselborg
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  5. Klaus Schulze-Osthoff
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  6. Jindrich Cinatl Jr
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  7. Martin Michaelis
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  8. Oliver Werz
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Corresponding author

Correspondence to Oliver Werz.

Additional information

I. Tretiakova and D. Blaesius contributed equally to this work.

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Tretiakova, I., Blaesius, D., Maxia, L. et al. Myrtucommulone from Myrtus communis induces apoptosis in cancer cells via the mitochondrial pathway involving caspase-9. Apoptosis 13, 119–131 (2008). https://doi.org/10.1007/s10495-007-0150-0

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  • DOI: https://doi.org/10.1007/s10495-007-0150-0

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