Skip to main content

Advertisement

SpringerLink
Log in

Synthetic triterpenoids inhibit growth and induce apoptosis in human glioblastoma and neuroblastoma cells through inhibition of prosurvival Akt, NF-κB and Notch1 signaling

  • Lab investigation-human/animal tissue
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Glioblastomas are high-risk primary brain tumors that are generally unresponsive or only weakly responsive to the currently available antineoplastic agents. Thus novel therapeutic strategies and agents are urgently needed to treat these incurable cancers. Oleanolic acid and ursolic acid are naturally occurring triterpenoids that have been used in traditional Asian medicine as anti-inflammatory and anti-cancer agents. Recently, synthetic oleanolic acid triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and its C-28 methyl ester (CDDO-Me) and C-28 imidazole (CDDO-Im) derivatives have been shown to exhibit potent antitumor activity against diverse types of tumor cell lines, including leukemia, multiple myeloma, osteosarcoma, breast, lung, and pancreatic cancer cell lines; however, the anticancer activity of these agents for brain tumors has not been reported. In the present study, we investigated the apoptosis-inducing activity of CDDOs in glioblastoma (U87MG, U251MG) and neuroblastoma (SK-N-MC) cell lines. Cell growth/viability (MTS) and cytotoxicity (LDH release) assays demonstrated that glioblastoma cell lines are least sensitive to CDDO, but are highly sensitive to CDDO-Me and CDDO-Im at concentrations of 2.5–10 μM. CDDO-Im and CDDO-Me were equipotenent in their growth inhibitory activity. The primary mode of tumor cell destruction was apoptosis as demonstrated by significant increase in the number of hypo-diploid (sub-G0) cells and annexin V-FITC binding. Induction of apoptosis was associated with the activation of procaspases-3, -8, and -9, mitochondrial depolarization and the release of cytochrome c from mitochondria. Furthermore, CDDO-Me inhibited the levels of anti-apoptotic and prosurvival p-Akt, NF-κB (p65) and Notch1 signaling molecules. These studies provide rationale for clinical evaluation of these novel agents for the management of lethal brain neoplasms.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Hosli P, Sappino A, de Tribolet N, Dietrich P (1998) Ann Oncol 9:589–600

    Google Scholar 

  2. DeAngelis LM, Burger PC, Green SB, Caironcross JG (1998) Malignant glioma: who benefits from adjuvant chemotherapy. Ann Neurol 44:691–695

    Article  PubMed  CAS  Google Scholar 

  3. Fine HA, Dear KB, Loeffler JS, Black PM, Canellos GP (1993) Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Caner 71:2585–2597

    Article  CAS  Google Scholar 

  4. Kim TS, Halliday AL, Hedley-Whyte ET, Convey K (1991) Correlates of survival and the Dumas-Duport grading system for astrocytomas. J Neurosurg 74:27–37

    PubMed  CAS  Google Scholar 

  5. Shapiro WR, Green SB, Burger PC, Maheley MS Jr, Selker RG, VanGilder JC, Robertson JT, Ransohoff J, Mealey J Jr, Strike TA et al (1989) Randomized trials of three chemotherapy regimens and two radiotherapy regimens in postoperative treatment of malignant gliomas. J Neurosurg 71:1–9

    Article  PubMed  CAS  Google Scholar 

  6. Arceci RJ (1995) Mechanism of resistance to therapy and tumor survival. Curr Opin Hematol 2:268–274

    Article  PubMed  CAS  Google Scholar 

  7. Denmeade SR, Lin XS, Isaacs JT (1996) Role of programmed (apoptotic) cell death during the progression and therapy for prostate cancer. Prostate 28:251–265

    Article  PubMed  CAS  Google Scholar 

  8. Kerr JF, Winterford CM, Harmon BV (1994) Apoptosis. Its significance in cancer and cancer therapy. Cancer 73:2013–2026

    CAS  Google Scholar 

  9. Rieger J, Naumann U, Glaser T, Ashkenazi A, Weller M (1998) APO2 ligand: a novel lethal weapon against malignant glioma? FEBS Lett 427:124–128

    Article  PubMed  CAS  Google Scholar 

  10. Knight MJ, Riffkin CD, Muscat AM, Ashley DM, Hawkins CJ (2001) Analysis of FasL and TRAIL induced apoptosis pathways in glioma cells. Oncogene 20:5789–5798

    Article  PubMed  CAS  Google Scholar 

  11. Pollack IF, Erff M, Ashkenazi A (2001) Direct stimulation of apoptotic signaling by soluble apo2L/tumor necrosis factor-related apoptosis-inducing ligand leads to selective killing of glioma cells. Clin Cancer Res 7:1362–1369

    PubMed  CAS  Google Scholar 

  12. Sporn MB, Suh N (2000) Chemoprevention of cancer. Carcinogenesis 21:525

    Article  PubMed  CAS  Google Scholar 

  13. Huang MT, Ho CT, Wang ZY, Ferraro T, Lou YR, Stauber K, Ma W, Georgiadis C, Laskin JD, Conney AH (1994) Inhibition of skin tumorigenesis by rosemary and its constituents carnosol and ursolic acid. Cancer Res 54:701

    PubMed  CAS  Google Scholar 

  14. Nishino H, Nishino A, Takayasu J, Hasegawa T, Iwashima A, Hirabayashi K, Iwata S, Shibata S (1988) Inhibition of the tumor-promoting action of 12-O-tetradecanoylphorbol-13-accetate by some oleanane-type triterpenoid compounds. Cancer Res 48:5210

    PubMed  CAS  Google Scholar 

  15. Ryu SY, Oak MH, Yoon SK, Cho DI, Yoo GS, Kim TS, Kim KM (2000) Anti-allergic and anti-inflammatory triterpenes from the herb of Prunella vulgaris. Planta Med 66:358

    Article  PubMed  CAS  Google Scholar 

  16. Suh N, Wang Y, Honda T, Gribble GW, Dmitrovsky E, Hickey WF et al (1998) Design and synthesis of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, a novel and highly active inhibitor of nitric oxide production in mouse macrophages. Biorg Med Chem Lett 8:2711

    Article  Google Scholar 

  17. Suh N, Honda T, Finlay HJ, Barchowsky A, Williams C, Benoit NE, Xie QW, Nathan C, Gribble GW, Sporn MB (1998) Triterpenoids suppress inducible nitric oxide synthase (iNOS) and inducible cyclooxigenase (COX-2) in mouse macrophages. Cancer Res 58:717

    PubMed  CAS  Google Scholar 

  18. Honda T, Rounds BV, Bore L, Favaloro FG, Gibble GW, Suh N, Wang Y, Sporn MB (1999) Novel synthetic oleanane triterpenoids: a series of highly active inhibitors of nitric oxide production in mouse macrophages. Bioorg Chem Lett 9:3429

    Article  CAS  Google Scholar 

  19. Suh N, Wang Y, Honda T, Gribble GW, Dmitrovsky E, Hickey WF, Maue RA, Place AE, Porter DM, Spinella MJ, Williams CR, Wu G, Dannenberg AJ, Flanders KC, Letterio JJ, Mangelsdorf DJ, Nathan CF, Nguyen L, Porter WW, Ren RF, Roberts AB, Roche NS, Subbaramaiah K, Sporn MB (1999) A novel synthetic oleanane triterpenoid, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, with potent differentiating, antiproliferative, and anti-inflammatory activity. Cancer Res. 59:336–341

    PubMed  CAS  Google Scholar 

  20. Konopleva M, Tsao T, Ruvolo P, Stiouf I, Estrov Z, Leysath CE, Zhao S, Harris D, Chang S, Jackson CE, Munsell M, Suh N, Gribble G, Honda T, May WS, Sporn MB, Andreeff M (2002) Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia. Blood 99:326–335

    Article  PubMed  CAS  Google Scholar 

  21. Shishodia S, Sethi G, Konopleva M, Andreeff M, Aggarwal BB (2006) A synthetic triterpenoid, CDDO-Me, inhibits IkappaBalpha kinase and enhances apoptosis induced by TNF and chemotherapeutic agents through down-regulation of expression of nuclear factor kappaB-regulated gene products in human leukemic cells. Clin Cancer Res12:1828–1838

    Article  Google Scholar 

  22. Ikeda T, Sporn M, Honda T, Gribble GW, Kufe D (2003) The novel triterpenoid CDDO and its derivatives induce apoptosis by disruption of intracellular redox balance. Cancer Res 63(17):5551–5558

    PubMed  Google Scholar 

  23. Konopleva M, Tsao T, Estrov Z, Lee RM, Wang RY, Jackson CE, McQueen T, Monaco G, Munsell M, Belmont J, Kantarjian H, Sporn MB, Andreeff M (2004) The synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces caspase-dependent and -independent apoptosis in acute myelogenous leukemia. Cancer Res 64:7927–7935

    Article  PubMed  CAS  Google Scholar 

  24. Ito Y, Pandey P, Sporn MB, Datta R, Kharbanda S, Kufe D (2001) The novel triterpenoid CDDO induces apoptosis and differentiation of human osteosarcoma cells by a caspase-8 dependent mechanism. Mol Pharmacol 59:1094–1099

    PubMed  CAS  Google Scholar 

  25. Konopleva M, Contractor R, Kurinna SM, Chen W, Andreeff M, Ruvolo PP (2005) The novel triterpenoid CDDO-Me suppresses MAPK pathways and promotes p38 activation in acute myeloid leukemia cells. Leukemia 19:1350–1354

    Article  PubMed  CAS  Google Scholar 

  26. Suh N, Roberts AB, Birkey Reffey S, Miyazono K, Itoh S, ten Dijke P, Heiss EH, Place AE, Risingsong R, Williams CR, Honda T, Gribble GW, Sporn MB (2003) Synthetic triterpenoids enhance transforming growth factor beta/Smad signaling. Cancer Res 63:1371–1376

    PubMed  CAS  Google Scholar 

  27. Chintharlapalli S, Papineni S, Konopleva M, Andreef M, Samudio I, Safe S (2005) 2-Cyano-3,12-dioxoolean-1,9-dien-28-oic acid and related compounds inhibit growth of colon cancer cells through peroxisome proliferator-activated receptor gamma-dependent and -independent pathways. Mol Pharmacol 68:119–128

    PubMed  CAS  Google Scholar 

  28. Zou W, Liu X, Yue P, Zhou Z, Sporn MB, Lotan R, Khuri FR, Sun SY (2004) c-Jun NH2-terminal kinase-mediated up-regulation of death receptor 5 contributes to induction of apoptosis by the novel synthetic triterpenoid methyl-2-cyano-3,12-dioxooleana-1, 9-dien-28-oate in human lung cancer cells. Cancer Res 64:7570–7578

    Article  PubMed  CAS  Google Scholar 

  29. Place AE, Suh N, Williams CR, Risingsong R, Honda T, Honda Y, Gribble GW, Leesnitzer LM, Stimmel JB, Willson TM, Rosen E, Sporn MB (2003) The novel synthetic triterpenoid, CDDO-imidazolide, inhibits inflammatory response and tumor growth in vivo. Clin Cancer Res 9:2798–2806

    PubMed  CAS  Google Scholar 

  30. Hyer ML, Croxton R, Krajewska M, Krajewski S, Kress CL, Lu M, Suh N, Sporn MB, Cryns VL, Zapata JM, Reed JC (2005) Synthetic triterpenoids cooperate with tumor necrosis factor-related apoptosis-inducing ligand to induce apoptosis of breast cancer cells. Cancer Res 65:4799–4808

    Article  PubMed  CAS  Google Scholar 

  31. Fan X, Mikolaenko I, Elhassan I, Ni X, Wang Y, Ball D, Brat DJ, Perry A, Eberhart CG (2004) Notch1 and notch2 have opposite effects on embryonal brain tumor growth. Cancer Res 65:2353–2363

    Article  Google Scholar 

  32. Purow BW, Haque RM, Noel MW, Su Q, Burdick MJ, Lee J, Sundaresan T, Pastorino S, Park JK, Mikolaenko I, Maric D, Eberhart CG, Fine HA (2005) Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation. Cancer Res 65:2353–2363

    Article  PubMed  CAS  Google Scholar 

  33. Sun X-M, MacFarlane M, Zhuang J, Wolf BB, Green DR, Cohen GM (1999) Distinct caspase cascades are initiated in receptor-mediated and chemical-induced apoptosis. J Biol Chem 27:4053–5060

    Google Scholar 

  34. Ashkenazi A, Dixit VM (1998) Death receptors: signaling and modulation. Science 28:1305–1308

    Article  Google Scholar 

  35. Luo X, Budihardjo I, Zou H, Slaughter C, Wang X (1998) Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 9:481–490

    Article  Google Scholar 

  36. Marte BM, Downward J (1997) PKB/Akt: connecting phosphoinositide3-kinase to cell survival and beyond. Trends Biochem Sci 22:355–358

    Article  PubMed  CAS  Google Scholar 

  37. Altomare DA, Testa JR (2005) Perturbations of the Akt signaling pathway in human cancer. Oncogene 24:7455–7464

    Article  PubMed  CAS  Google Scholar 

  38. Karin M, Cao Y, Greten FR, Li Z-W (2002) NF-κB in cancer. From innocent bystander to major culprit. Nature Rev Cancer 2:301–310

    CAS  Google Scholar 

  39. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME (1997) Akt phosphorylation of Bad couples survival signals to the cell-intrinsic death machinery. Cell 91:231–241

    Article  PubMed  CAS  Google Scholar 

  40. Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Standbridge E, Frisch S, Reed JC (1998) Regulation of cell death protease caspase-9 by phosphorylation. Science 282:1318–1321

    Article  PubMed  CAS  Google Scholar 

  41. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96:857–868

    Article  PubMed  CAS  Google Scholar 

  42. Baeurele PA, Henkel T (1994) Function and activation of NF-κB in the immune system. Annu Rev Immunol 12:141–179

    Google Scholar 

  43. Mayo MW, Baldwin AS (2000) The transcription factor NF-κB: control of oncogenesis and cancer therapy resistance. Biochim Biophys Acta 1470:M55–M62

    PubMed  CAS  Google Scholar 

  44. Weaver KD, Yeyeodu S, Cusack JC Jr, Baldwin AS Jr, Ewend MG (2003) Potentiation of chemotherapeutic agents following antagonism of nuclear factor kappa B in human gliomas. J Neurooncol 61:187–196

    Article  PubMed  Google Scholar 

  45. Cusack JC Jr (2003) Overcoming antiapoptotic responses to promote chemosensitivity in metastatic colorectal cancer to the liver. Ann Surg Oncol 10:852–862

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

Supported by USPHS Grants RO1 CA85976 and R21 CA102616 to S.C.G.

Author information

Authors and Affiliations

  1. Department of Surgery, Henry Ford Health System, Detroit, MI, USA

    Xiaohua Gao, Dorrah Deeb, Yongbo Liu, Scott A. Dulchavsky & Subhash C. Gautam

  2. Department of Neurology, Henry Ford Health System, Detroit, MI, USA

    Hao Jiang

Authors
  1. Xiaohua Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dorrah Deeb
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hao Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yongbo Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Scott A. Dulchavsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Subhash C. Gautam
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Subhash C. Gautam.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gao, X., Deeb, D., Jiang, H. et al. Synthetic triterpenoids inhibit growth and induce apoptosis in human glioblastoma and neuroblastoma cells through inhibition of prosurvival Akt, NF-κB and Notch1 signaling. J Neurooncol 84, 147–157 (2007). https://doi.org/10.1007/s11060-007-9364-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-007-9364-9

Keywords

Search

Navigation