Advertisement

Investigational New Drugs

, Volume 33, Issue 1, pp 64–74 | Cite as

Selective ROS-dependent p53-associated anticancer effects of the hypoxoside derivative rooperol on human teratocarcinomal cancer stem-like cells

  • Sarah Ali Azouaou
  • Fathi Emhemmed
  • Noureddine Idris-Khodja
  • Annelise Lobstein
  • Valérie Schini-Kerth
  • Christian D. Muller
  • Guy FuhrmannEmail author
PRECLINICAL STUDIES

Abstract

Cancer stem cells (CSCs) are potential targets for innovative anticancer therapies that involve natural products with potential chemopreventive effects. We therefore analyzed the antineoplastic activity of rooperol, the aglycone of the plant-derived compound hypoxoside, on a model of Oct4-expressing cancer stem-like cell, i.e. the human embryonal carcinoma (EC) cell NT2/D1.

Rooperol selectively inhibited the proliferation of NT2/D1 cells in a concentration-dependent manner and had no effect on either normal embryonic fibroblasts which are more restrictive pluripotent stem cells or on NCCIT p53-mutant EC cells. Accordingly, rooperol only eliminates colon carcinoma cells expressing p53.

Rooperol treatment triggered cell death on NT2/D1 cells through the alteration of mitochondrial membrane potential and production of reactive oxygen species (ROS). Rooperol-induced apoptosis was associated with activation of p53 and concentration-dependent changes of the expression levels of both caspase 3 and poly ADP ribose polymerase type 1 cleaved subunits. These modifications were accompanied by a downregulation of Oct4 and its two partners involved in the maintenance of cell pluripotency and self-renewal, Nanog and Sox2.

Treatment with intracellular membrane permeant O2 scavengers prevented rooperol-induced apoptosis and upregulation of the expression of p53 and active caspase-3. Our findings indicate that rooperol mediates its growth inhibitory effects on CSCs via a mitochondrial redox-sensitive mechanism. We propose that abrogating the expression of the stemness regulators is a prerequisite for rooperol to fully exert its pro-apoptotic properties on wild-type p53-bearing CSCs.

Keywords

Cancer stem-like cells Rooperol Apoptosis Reactive oxygen species p53 Oct4 

Notes

Acknowledgments

This work is dedicated to the memory of Dr. A.C. Allison. This study has been supported by grants from the CCIR-GE of the “Ligue contre le Cancer” (Comité du Grand Est, France). Fathi Emhemmed is supported by a fellowship from the Higher Education Commission of Libya.

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1.
    Sell S (2004) Stem cell origin of cancer and differentiation therapy. Crit Rev Oncol Hematol 51:1–28PubMedCrossRefGoogle Scholar
  2. 2.
    Sharif T, Emhemmed F, Fuhrmann G (2011) Towards new anticancer strategies by targeting cancer stem cells with phytochemical compounds. In: Shostak S (ed) Cancer Stem Cells - The Cutting Edge. Rijeka, Croatia, Intech, pp 431–456Google Scholar
  3. 3.
    Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA, Dick JE (1994) A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367:645–648PubMedCrossRefGoogle Scholar
  4. 4.
    Visvader JE (2011) Cells of origin in cancer. Nature 469:314–322PubMedCrossRefGoogle Scholar
  5. 5.
    Surh YJ (2003) Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer 3:768–780PubMedCrossRefGoogle Scholar
  6. 6.
    Chabner BA, Roberts TG Jr (2005) Timeline: Chemotherapy and the war on cancer. Nat Rev Cancer 5:65–72PubMedCrossRefGoogle Scholar
  7. 7.
    Shu L, Cheung KL, Khor TO, Chen C, Kong AN (2010) Phytochemicals: cancer chemoprevention and suppression of tumor onset and metastasis. Cancer Metastasis Rev 29:483–502PubMedCrossRefGoogle Scholar
  8. 8.
    Sharif T, Auger C, Bronner C, Alhosin M, Klein T, Etienne-Selloum N, Schini-Kerth VB, Fuhrmann G (2011) Selective proapoptotic activity of polyphenols from red wine on teratocarcinoma cell, a model of cancer stem-like cell. Invest New Drugs 29:239–247PubMedCrossRefGoogle Scholar
  9. 9.
    Sharif T, Stambouli M, Burrus B, Emhemmed F, Dandache I, Auger C, Etienne-Selloum N, Schini-Kerth VB, Fuhrmann G (2013) The polyphenolic-rich Aronia melanocarpa juice kills teratocarcinomal cancer stem-like cells, but not their differentiated counterparts. J Funct Foods 5:1244–1252CrossRefGoogle Scholar
  10. 10.
    Emhemmed F, Ali Azouaou S, Thuaud F, Schini-Kerth V, Désaubry L, Muller CD, Fuhrmann G (2014) Selective anticancer effects of a synthetic flavagline on human Oct4-expressing cancer stem-like cells via a p38 MAPK-dependent caspase-3-dependent pathway. Biochem Pharmacol 89:185–196PubMedCrossRefGoogle Scholar
  11. 11.
    Guzdek A, Turyna B, Allison AC, Sladek K, Koj A (1997) Rooperol, an inhibitor of cytokine synthesis, decreases the respiratory burst in human and rat leukocytes and macrophages. Mediators Inflamm 6:53–57PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Boukes GJ, van de Venter M (2012) Rooperol as an antioxidant and its role in the innate immune system: an in vitro study. J Ethnopharmacol 144:692–699PubMedCrossRefGoogle Scholar
  13. 13.
    Boukes GJ, Daniels BB, Albrecht CF, van de Venter M (2010) Cell survival or apoptosis: rooperol’s role as anticancer agent. Oncol Res 18:365–376PubMedCrossRefGoogle Scholar
  14. 14.
    Pesce M, Schöler HR (2001) Oct-4: gatekeeper in the beginnings of mammalian development. Stem Cells 19:271–278PubMedCrossRefGoogle Scholar
  15. 15.
    Jung M, Peterson H, Chavez L, Kahlem P, Lehrach H, Vilo J, Adjaye J (2010) A data integration approach to mapping OCT4 gene regulatory networks operative in embryonic stem cells and embryonal carcinoma cells. PLoS One 5:e10709PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS, Zucker JP, Guenther MG, Kumar RM, Murray HL, Jenner RG, Gifford DK, Melton DA, Jaenisch R, Young RA (2005) Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122:947–956PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Kang J, Shakya A, Tantin D (2009) Stem cells, stress, metabolism and cancer: a drama in two Octs. Trends Biochem Sci 34:491–499PubMedCrossRefGoogle Scholar
  18. 18.
    Ben-Porath I, Thomson MW, Carey VJ, Ge R, Bell GW, Regev A, Weinberg RA (2008) An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 40:499–507PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Robinton DA, Daley GQ (2012) The promise of induced pluripotent stem cells in research and therapy. Nature 481:295–305PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Sharif T, Alhosin M, Auger C, Minker C, Kim JH, Etienne-Selloum N, Bories P, Gronemeyer H, Lobstein A, Bronner C, Fuhrmann G, Schini-Kerth VB (2012) Aronia melanocarpa juice induces a redox-sensitive p73-related caspase 3-dependent apoptosis in human leukemia cells. PLoS One 7:e32526PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Fuhrmann G, Sylvester I, Schöler HR (1999) Repression of Oct-4 during embryonic cell differentiation correlates with the appearance of TRIF, a transiently induced DNA-binding factor. Cell Mol Biol 45:717–724PubMedGoogle Scholar
  22. 22.
    Sharif T, Auger C, Alhosin M, Ebel C, Achour M, Etienne-Selloum N, Fuhrmann G, Bronner C, Schini-Kerth VB (2010) Red wine polyphenols cause growth inhibition and apoptosis in acute lymphoblastic leukaemia cells by inducing a redox-sensitive up-regulation of p73 and down-regulation of UHRF1. Eur J Cancer 46:983–994PubMedCrossRefGoogle Scholar
  23. 23.
    Sánchez-Duffhues G, Calzado MA, de Vinuesa AG, Appendino G, Fiebich BL, Loock U et al (2009) Denbinobin inhibits nuclear factor-kappaB and induces apoptosis via reactive oxygen species generation in human leukemic cells. Biochem Pharmacol 77:1401–1409PubMedCrossRefGoogle Scholar
  24. 24.
    Rodriguez R, Meuth M (2006) Chk1 and p21 cooperate to prevent apoptosis during DNA replication fork stress. Mol Biol Cell 17:402–412PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Roos WP, Kaina B (2006) DNA damage-induced cell death by apoptosis. Trends Mol Med 12:440–450PubMedCrossRefGoogle Scholar
  26. 26.
    Warburg O (1925) Uber den Stoffwechsel der Carcinomzelle. Klin Wochenschr Berl 4:534–536CrossRefGoogle Scholar
  27. 27.
    Zheng J (2012) Energy metabolism of cancer: Glycolysis versus oxidative phosphorylation. Oncol Lett 4:1151–1157PubMedCentralPubMedGoogle Scholar
  28. 28.
    Poyton RO, Ball KA, Castello PR (2009) Mitochondrial generation of free radicals and hypoxic signaling. Trends Endocrinol Metab 20:332–340PubMedCrossRefGoogle Scholar
  29. 29.
    Buettner GR (2011) Superoxide dismutase in redox biology: the roles of superoxide and hydrogen peroxide. Anticancer Agents Med Chem 11:341–346PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Hochedlinger K, Yamada Y, Beard C, Jaenisch R (2005) Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues. Cell 121:465–477PubMedCrossRefGoogle Scholar
  31. 31.
    Wang YD, Cai N, Wu XL, Cao HZ, Xie LL, Zheng PS (2013) OCT4 promotes tumorigenesis and inhibits apoptosis of cervical cancer cells by miR-125b/BAK1 pathway. Cell Death Dis 4:e760PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Sarah Ali Azouaou
    • 1
    • 2
  • Fathi Emhemmed
    • 1
    • 2
  • Noureddine Idris-Khodja
    • 1
    • 3
  • Annelise Lobstein
    • 2
  • Valérie Schini-Kerth
    • 1
  • Christian D. Muller
    • 2
  • Guy Fuhrmann
    • 1
    Email author
  1. 1.UMR 7213 CNRS, Laboratoire de Biophotonique et Pharmacologie, Faculté de PharmacieUniversité de StrasbourgIllkirchFrance
  2. 2.UMR 7200 CNRS, Laboratoire d’Innovation Thérapeutique, Faculté de PharmacieUniversité de StrasbourgIllkirchFrance
  3. 3.Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General HospitalMcGill UniversityMontrealCanada

Personalised recommendations