Skip to main content

Advertisement

SpringerLink
Log in

CDDO-Me, a synthetic triterpenoid, inhibits expression of IL-6 and Stat3 phosphorylation in multi-drug resistant ovarian cancer cells

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Previous studies have identified interleukin 6 (IL-6) as an important cytokine with prognostic significance in ovarian cancer. Activation of the IL-6-Stat3 pathway contributes to tumor cell growth, survival and drug resistance in several cancers, including ovarian cancer. To explore potential therapeutic strategies for interrupting signaling through this pathway, we assessed the ability of CDDO-Me, a synthetic triterpenoid, to inhibit IL-6 secretion, Stat3 phosphorylation, Stat3 nuclear translocation and paclitaxel sensitivity in several cell line model systems. These studies demonstrated that CDDO-Me significantly inhibits IL-6 secretion in paclitaxel-resistant ovarian cancer cells and specifically suppresses IL-6- or oncostatin M-induced Stat3 nuclear translocation. Treatment with CDDO-Me significantly decreases the levels of Stat3, Jak2, and Src phosphorylation in ovarian and breast cancer cell lines with constitutively activated Stat3. This inhibition of the IL-6-Stat3 pathway correlated with suppression of the anti-apoptotic Stat3 target genes Bcl-XL, survivin, and Mcl-1, and with apoptosis induction as measured by monitoring PARP and its cleavage product, as well as by quantitative measurement of the apoptosis-associated CK18Asp396. Furthermore, CDDO-Me increases the cytotoxic effects of paclitaxel in the paclitaxel-resistant ovarian cancer cell line OVCAR8TR (2 to 5-fold) and of cisplatin in the cisplatin-resistant ovarian cancer cell line A2780cp70 (2 to 4-fold). Our data confirm that CDDO-Me interrupts the signaling of multiple kinases involved in the IL-6-Stat3 and Src signaling pathways. Inhibition is likely achieved through multiple points within these pathways. In a model system of established acquired drug resistance, CCDO-Me is effective at partially reversing the drug-resistance phenotype.

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

Similar content being viewed by others

References

  1. Ahmad R, Raina D, Meyer C, Kharbanda S, Kufe D (2006) Triterpenoid CDDO-Me blocks the NF-kappaB pathway by direct inhibition of IKKbeta on Cys-179. J Biol Chem 281:35764–35769

    Article  PubMed  CAS  Google Scholar 

  2. Barre B, Vigneron A, Perkins N, Roninson IB, Gamelin E, Coqueret O (2006) The STAT3 oncogene as a predictive marker of drug resistance. Trends Mol Med 13:4–11

    Article  PubMed  Google Scholar 

  3. Carmichael J, DeGraff WG, Gazdar AF, Minna JD, Mitchell JB (1987) Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of radiosensitivity. Cancer Res 47:943–946

    PubMed  CAS  Google Scholar 

  4. Chauhan D, Uchiyama H, Akbarali Y, Urashima M, Yamamoto K, Libermann TA, Anderson KC (1996) Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B. Blood 87:1104–1112

    PubMed  CAS  Google Scholar 

  5. Darnell JE Jr (1997) STATs and gene regulation. Science 277:1630–1635

    Article  PubMed  CAS  Google Scholar 

  6. Diaz N, Minton S, Cox C, Bowman T, Gritsko T, Garcia R, Eweis I, Wloch M, Livingston S, Seijo E, Cantor A, Lee JH, Beam CA, Sullivan D, Jove R, Muro-Cacho CA (2006) Activation of stat3 in primary tumors from high-risk breast cancer patients is associated with elevated levels of activated SRC and survivin expression. Clin Cancer Res 12:20–28

    Article  PubMed  CAS  Google Scholar 

  7. Duan Z, Feller AJ, Penson RT, Chabner BA, Seiden MV (1999) Discovery of differentially expressed genes associated with paclitaxel resistance using cDNA array technology: analysis of interleukin (IL) 6, IL-8, and monocyte chemotactic protein 1 in the paclitaxel-resistant phenotype. Clin Cancer Res 5:3445–3453

    PubMed  CAS  Google Scholar 

  8. Duan Z, Foster R, Bell D, Mahoney J, Wolak K, Vaidya A, Hampel C, Lee E, Seiden MV (2006) Signal transducers and activators of transcription 3 pathway activation in drug-resistant ovarian cancer. Clin Cancer Res 12:5055–5063

    Article  PubMed  CAS  Google Scholar 

  9. Duan Z, Lamendola DE, Duan Y, Yusuf RZ, Seiden MV (2005) Description of paclitaxel resistance-associated genes in ovarian and breast cancer cell lines. Cancer Chemother Pharmacol 55:277–285

    Article  PubMed  CAS  Google Scholar 

  10. Duan Z, Lamendola DE, Penson RT, Kronish KM, Seiden MV (2002) Overexpression of IL-6 but not IL-8 increases paclitaxel resistance of U-2OS human osteosarcoma cells. Cytokine 17:234–242

    Article  PubMed  CAS  Google Scholar 

  11. Erdal H, Berndtsson M, Castro J, Brunk U, Shoshan MC, Linder S (2005) Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis. Proc Natl Acad Sci USA 102:192–197

    Article  PubMed  CAS  Google Scholar 

  12. Gritsko T, Williams A, Turkson J, Kaneko S, Bowman T, Huang M, Nam S, Eweis I, Diaz N, Sullivan D, Yoder S, Enkemann S, Eschrich S, Lee JH, Beam CA, Cheng J, Minton S, Muro-Cacho CA, Jove R (2006) Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin Cancer Res 12:11–19

    Article  PubMed  CAS  Google Scholar 

  13. Hideshima T, Chauhan D, Richardson P, Mitsiades C, Mitsiades N, Hayashi T, Munshi N, Dang L, Castro A, Palombella V, Adams J, Anderson KC (2002) NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 277:16639–16647

    Article  PubMed  CAS  Google Scholar 

  14. Hodge DR, Hurt EM, Farrar WL (2005) The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer 41:2502–2512

    Article  PubMed  CAS  Google Scholar 

  15. 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 

  16. Liby K, Royce DB, Williams CR, Risingsong R, Yore MM, Honda T, Gribble GW, Dmitrovsky E, Sporn TA, Sporn MB (2007) The synthetic triterpenoids CDDO-methyl ester and CDDO-ethyl amide prevent lung cancer induced by vinyl carbamate in A/J mice. Cancer Res 67:2414–2419

    Article  PubMed  CAS  Google Scholar 

  17. Liby KT, Yore MM, Sporn MB (2007) Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer. Nat Rev Cancer 7:357–369

    Article  PubMed  CAS  Google Scholar 

  18. Meinhold-Heerlein I, Bauerschlag D, Hilpert F, Dimitrov P, Sapinoso LM, Orlowska-Volk M, Bauknecht T, Park TW, Jonat W, Jacobsen A, Sehouli J, Luttges J, Krajewski M, Krajewski S, Reed JC, Arnold N, Hampton GM (2005) Molecular and prognostic distinction between serous ovarian carcinomas of varying grade and malignant potential. Oncogene 24:1053–1065

    Article  PubMed  CAS  Google Scholar 

  19. Nilsson MB, Langley RR, Fidler IJ (2005) Interleukin-6, secreted by human ovarian carcinoma cells, is a potent proangiogenic cytokine. Cancer Res 65:10794–10800

    Article  PubMed  CAS  Google Scholar 

  20. Penson RT, Kronish K, Duan Z, Feller AJ, Stark P, Cook SE, Duska LR, Fuller AF, Goodman AK, Nikrui N, MacNeill KM, Matulonis UA, Preffer FI, Seiden MV (2000) Cytokines IL-1beta, IL-2, IL-6, IL-8, MCP-1, GM-CSF and TNFalpha in patients with epithelial ovarian cancer and their relationship to treatment with paclitaxel. Int J Gynecol Cancer 10:33–41

    Article  PubMed  Google Scholar 

  21. Plante M, Rubin SC, Wong GY, Federici MG, Finstad CL, Gastl GA (1994) Interleukin-6 level in serum and ascites as a prognostic factor in patients with epithelial ovarian cancer. Cancer 73:1882–1888

    Article  PubMed  CAS  Google Scholar 

  22. Rosen DG, Mercado-Uribe I, Yang G, Bast RC Jr, Amin HM, Lai R, Liu J (2006) The role of constitutively active signal transducer and activator of transcription 3 in ovarian tumorigenesis and prognosis. Cancer 107:2730–2740

    Article  PubMed  CAS  Google Scholar 

  23. Savarese TM, Campbell CL, McQuain C, Mitchell K, Guardiani R, Quesenberry PJ, Nelson BE (2002) Coexpression of oncostatin M and its receptors and evidence for STAT3 activation in human ovarian carcinomas. Cytokine 17:324–334

    Article  PubMed  CAS  Google Scholar 

  24. 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 Res 12:1828–1838

    Article  PubMed  CAS  Google Scholar 

  25. Silver DL, Naora H, Liu J, Cheng W, Montell DJ (2004) Activated signal transducer and activator of transcription (STAT) 3: localization in focal adhesions and function in ovarian cancer cell motility. Cancer Res 64:3550–3558

    Article  PubMed  CAS  Google Scholar 

  26. Yore MM, Liby KT, Honda T, Gribble GW, Sporn MB (2006) The synthetic triterpenoid 1-[2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oyl]imidazole blocks nuclear factor-kappaB activation through direct inhibition of IkappaB kinase beta. Mol Cancer Ther 5:3232–3239

    Article  PubMed  CAS  Google Scholar 

  27. Yu H, Jove R (2004) The STATs of cancer–new molecular targets come of age. Nat Rev Cancer 4:97–105

    Article  PubMed  CAS  Google Scholar 

  28. Yu H, Kortylewski M, Pardoll D (2007) Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 7:41–51

    Article  PubMed  CAS  Google Scholar 

  29. Yusuf RZ, Duan Z, Lamendola DE, Penson RT, Seiden MV (2003) Paclitaxel resistance: molecular mechanisms and pharmacologic manipulation. Curr Cancer Drug Targets 3:1–19

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This project was supported by the Ovarian Cancer SPORE at the DF/HCC 1P50CA105009, and a Grant from the Ovarian Cancer Education and Awareness Network (OCEAN). Dr. Duan is supported, in part, through a grant from the Marsha Rivkin Ovarian Cancer Research Foundation and Wechsler fund. Dr. Seiden is supported by a Mid Career Development Award, 1K24 CA109416-01A1. In addition, we would like to acknowledge Dr. Donald Kufe at Dana-Farber Cancer Institute for providing useful advices during the drafting of this manuscript.

Author information

Authors and Affiliations

  1. Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, 100 Blossom St. Jackson 1115, Boston, MA, 02114, USA

    Zhenfeng Duan, Meagan Ryan, Francis J. Hornicek & Henry Mankin

  2. Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA

    Rachel Y. Ames

  3. Fox Chase Cancer Center, Philadelphia, PA, USA

    Michael V. Seiden

Authors
  1. Zhenfeng Duan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rachel Y. Ames
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Meagan Ryan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Francis J. Hornicek
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Henry Mankin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael V. Seiden
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhenfeng Duan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Duan, Z., Ames, R.Y., Ryan, M. et al. CDDO-Me, a synthetic triterpenoid, inhibits expression of IL-6 and Stat3 phosphorylation in multi-drug resistant ovarian cancer cells. Cancer Chemother Pharmacol 63, 681–689 (2009). https://doi.org/10.1007/s00280-008-0785-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-008-0785-8

Keywords

Search

Navigation