Skip to main content
SpringerLink
Log in

5-Fluorouracil prevents lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophage cells by inhibiting Akt-dependent nuclear factor-κB activation

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

Abstract

The effect of 5-fluorouracil (5-FU) on the production of nitric oxide (NO) in macrophages was examined by using lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. 5-FU at non-toxic concentrations significantly inhibited NO production in LPS-stimulated RAW 264.7 cells. The inhibition by 5-FU was mediated by attenuated expression of an inducible NO synthase protein and mRNA. 5-FU inhibited the activation of nuclear factor (NF)-κB and the subsequent nuclear translocation. Furthermore, 5-FU inhibited the phosphorylation of Akt, an upstream molecule of NF-κB signaling. 5-FU did not affect a series of mitogen-activated protein kinases. Therefore, 5-FU was suggested to inhibit the LPS-induced NO production in activated macrophages through preventing Akt-dependent NF-κB activation.

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. Albina JE, Reichner JS (1998) Role of nitric oxide in mediation of macrophage cytotoxicity and apoptosis. Cancer Metastasis Rev 17:39–53

    Article  PubMed  CAS  Google Scholar 

  2. Lechner M, Lirk P, Rieder J (2005) Inducible nitric oxide synthase (iNOS) in tumor biology: the two sides of the same coin. Semin Cancer Biol 15:277–289

    Article  PubMed  CAS  Google Scholar 

  3. Xu W, Liu LZ, Loizidou M, Ahmed M, Charles IG (2002) The role of nitric oxide in cancer. Cell Res 12:311–320

    Article  PubMed  Google Scholar 

  4. Malet-Martino M, Jolimaitre P, Martino R (2002) The prodrugs of 5-fluorouracil. Curr Med Chem Anti-Cancer Agents 2:267–310

    Article  CAS  Google Scholar 

  5. JinY, Heck DE, DeGeorge G, Tian Y, Laskin JD (1996) 5-Fluorouracil suppresses nitric oxide biosynthesis in colon carcinoma cells. Cancer Res 56:1978–1982

    PubMed  Google Scholar 

  6. Jung ID, Yang SY, Park CG, Lee KB, Kim JS, Lee SY, Han JW, Lee HW, Lee HY (2002) 5-Fluorouracil inhibits nitric oxide production through the inactivation of IkappaB kinase in stomach cancer cells. Biochem Pharmacol 64:1439–1445

    Article  PubMed  CAS  Google Scholar 

  7. Oshima T, Imada T, Nagashima Y, Cho H, Shiozawa M, Rino Y, Takanashi Y (2001) Role of nitric oxide in human gastric cancer cells treated with 5-fluorouracil. Oncol Rep 8:847–849

    PubMed  CAS  Google Scholar 

  8. Jiang J, Liu J, Zhu J, Yang C, Zhang A (2002) Mechanism of apoptotic effects induced by 5-fluorouracil on human liver carcinoma Bel7402 cell line. Chin Med J 115:968–971

    PubMed  CAS  Google Scholar 

  9. Xie QW, Whisnant R, Nathan C (1993) Promoter of the mouse gene encoding calcium-independent nitric oxide synthase confers inducibility by interferon gamma and bacterial lipopolysaccharide. J Exp Med 177:1779–1784

    Article  PubMed  CAS  Google Scholar 

  10. Liu S, Adcock IM, Old RW, Barnes PJ, Evans TW (1993) Lipopolysaccharide treatment in vivo induces widespread tissue expression of inducible nitric oxide synthase mRNA. Biochem Biophys Res Commun 196:1208–1213

    Article  PubMed  CAS  Google Scholar 

  11. Hanelt M, Gareis M, Kollarczik B (1994) Cytotoxicity of mycotoxins evaluated by the MTT-cell culture assay. Mycopathologia 128:167–174

    Article  PubMed  CAS  Google Scholar 

  12. Green LC, Wagner DDA, Glowgowski J, Skepper PL, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite and 15N nitrate in biological fluids. Anal Biochem 1236:131–138

    Article  Google Scholar 

  13. Islam S, Hassan F, Mu MM, Ito H, Koide N, Mori I, Yoshida T, Yokochi T (2004) Piceatannol prevents lipopolysaccharide (LPS)-induced nitric oxide (NO) production and nuclear factor (NF)-kappaB activation by inhibiting IkappaB kinase (IKK). Microbiol Immunol 48:729–736

    PubMed  CAS  Google Scholar 

  14. Romashkova JA, Makarov SS (1999) NF-kappaB is a target of AKT in anti-apoptotic PDGF signaling. Nature 401:86–90

    Article  PubMed  CAS  Google Scholar 

  15. DeFranco AL, Hambleton J, McMahon M, Weinstein SL (1995) Examination of the role of MAP kinase in the response of macrophages to lipopolysaccharide. Prog Clin Biol Res 392:407–420

    PubMed  CAS  Google Scholar 

  16. Guha M, Mackman N (2001) LPS induction of gene expression in human monocytes. Cell Signal 13:85–94

    Article  PubMed  CAS  Google Scholar 

  17. Lala PK, Orucevic A (1998) Role of nitric oxide in tumor progression: lessons from experimental tumors. Cancer Metastasis Rev 17:91–106

    Article  PubMed  CAS  Google Scholar 

  18. Ekmekcioglu S, Tang CH, Grimm EA (2005) NO news is not necessarily good news in cancer. Curr Cancer Drug Targets 5:103–115

    Article  PubMed  CAS  Google Scholar 

  19. Azuma M, Yamashita T, Aota K, Tamatani T, Sato M (2001) 5-Fluorouracil suppression of NF-KappaB is mediated by the inhibition of IKappab kinase activity in human salivary gland cancer cells. Biochem Biophys Res Commun 282:292–296

    Article  PubMed  CAS  Google Scholar 

  20. Fresno Vara JA, Casado E, De Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M (2004) PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 30:193–204

    Article  PubMed  CAS  Google Scholar 

  21. Nicholson KM, Anderson NG (2002) The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal 14:381–395

    Article  PubMed  CAS  Google Scholar 

  22. Kim D, Dan HC, Park S, Yang L, Liu Q, Kaneko S, Ning J, He L, Yang H, Sun M, Nicosia SV, Cheng JQ (2005) AKT/PKB signaling mechanisms in cancer and chemoresistance. Front Biosci 10:975–987

    PubMed  CAS  Google Scholar 

  23. Cheng JQ, Lindsley CW, Cheng GZ, Yang H, Nicosia SV (2005) The Akt/PKB pathway: molecular target for cancer drug discovery. Oncogene 24:7482–7492

    Article  PubMed  CAS  Google Scholar 

  24. Baldwin AS Jr (1996) NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol 14:649–683

    Article  PubMed  CAS  Google Scholar 

  25. Muller JM, Ziegler-Heitbrock HW, Baeuerle PA (1993) Nuclear factor kappa B, a mediator of lipopolysaccharide effects. Immunobiology 187:233–256

    PubMed  CAS  Google Scholar 

  26. Kawai T, Takeuchi O, Fujita T, Inoue J, Muhlradt PF, Sato S, Hoshino K, Akira S (2001) Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J Immunol 167:5887–5894

    PubMed  CAS  Google Scholar 

  27. Toshchakov V, Jones BW, Perera PY, Thomas K, Cody MJ, Zhang S, Williams BR, Major J, Hamilton TA, Fenton MJ, Vogel SN (2002) TLR4, but not TLR2, mediates IFN-beta-induced STAT1alpha/beta-dependent gene expression in macrophages. Nat Immunol 3:392–398

    Article  PubMed  CAS  Google Scholar 

  28. Weinstein SL, Finn AJ, Dave SH, Meng F, Lowell CA, Sanghera JS, DeFranco AL (2000) Phosphatidylinositol 3-kinase and mTOR mediate lipopolysaccharide-stimulated nitric oxide production in macrophages via interferon-beta. J Leukoc Biol 67:405–414

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported in part by a Grant-in-Aid for Scientific Research (KAKENHI 14570247). We are grateful to K. Takahashi and A. Morikawa for the technical assistance.

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi, 480-1195, Japan

    Shamima Islam, Ferdaus Hassan, Gantsetseg Tumurkhuu, Hiroyasu Ito, Naoki Koide, Isamu Mori, Tomoaki Yoshida & Takashi Yokochi

Authors
  1. Shamima Islam
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ferdaus Hassan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gantsetseg Tumurkhuu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroyasu Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Naoki Koide
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Isamu Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tomoaki Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Takashi Yokochi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takashi Yokochi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Islam, S., Hassan, F., Tumurkhuu, G. et al. 5-Fluorouracil prevents lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophage cells by inhibiting Akt-dependent nuclear factor-κB activation. Cancer Chemother Pharmacol 59, 227–233 (2007). https://doi.org/10.1007/s00280-006-0261-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-006-0261-2

Keywords

Search

Navigation