Logo of brjcancerBJC HomepageBJC Advance online publicationBJC Current IssueSubmitting an article to BJCWeb feeds
Br J Cancer. Jan 1999; 79(2): 257–263.
PMCID: PMC2362195

Tamoxifen induces oxidative stress and apoptosis in oestrogen receptor-negative human cancer cell lines

Abstract

Recent data have demonstrated that the anti-oestrogen tamoxifen (TAM) is able to facilitate apoptosis in cancer cells not expressing oestrogen receptor (ER). In an attempt to identify the biochemical pathway for this phenomenon, we investigated the role of TAM as an oxidative stress agent. In two ER-negative human cancer cell lines, namely T-leukaemic Jurkat and ovarian A2780 cancer cells, we have demonstrated that TAM is able to generate oxidative stress, thereby causing thiol depletion and activation of the transcriptional factor NF-κB. As described for other oxidative agents, TAM was able to induce either cell proliferation or apoptosis depending on the dose. When used at the lowest dose tested (0.1 μM), a slight proliferative effect of TAM was noticed in terms of cell counts and DNA synthesis rate, whereas at higher doses (10 μM) a consistent occurrence of apoptosis was detected. Importantly, the induction of apoptosis by TAM is not linked to down-regulation or functional inactivation by phosphorylation of the antiapoptotic bcl-2 protein. © 1999 Cancer Research Campaign

Keywords: oxidative stress, tamoxifen, apoptosis, NF-κB

Full Text

The Full Text of this article is available as a PDF (291K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Bass DA, Parce JW, Dechatelet LR, Szejda P, Seeds MC, Thomas M. Flow cytometric studies of oxidative product formation by neutrophils: a graded response to membrane stimulation. J Immunol. 1983 Apr;130(4):1910–1917. [PubMed]
  • Berman E, Adams M, Duigou-Osterndorf R, Godfrey L, Clarkson B, Andreeff M. Effect of tamoxifen on cell lines displaying the multidrug-resistant phenotype. Blood. 1991 Feb 15;77(4):818–825. [PubMed]
  • Couldwell WT, Hinton DR, He S, Chen TC, Sebat I, Weiss MH, Law RE. Protein kinase C inhibitors induce apoptosis in human malignant glioma cell lines. FEBS Lett. 1994 May 23;345(1):43–46. [PubMed]
  • De Vincenzo R, Scambia G, Benedetti Panici P, Fattorossi A, Bonanno G, Ferlini C, Isola G, Pernisco S, Mancuso S. Modulatory effect of tamoxifen and ICI 182,780 on adriamycin resistance in MCF-7 human breast-cancer cells. Int J Cancer. 1996 Nov 4;68(3):340–348. [PubMed]
  • Ferlini C, Biselli R, Scambia G, Fattorossi A. Probing chromatin structure in the early phases of apoptosis. Cell Prolif. 1996 Jul;29(7):427–436. [PubMed]
  • Ferlini C, Scambia G, Distefano M, Filippini P, Isola G, Riva A, Bombardelli E, Fattorossi A, Benedetti Panici P, Mancuso S. Synergistic antiproliferative activity of tamoxifen and docetaxel on three oestrogen receptor-negative cancer cell lines is mediated by the induction of apoptosis. Br J Cancer. 1997;75(6):884–891. [PMC free article] [PubMed]
  • Gosland M, Lum B, Schimmelpfennig J, Baker J, Doukas M. Insights into mechanisms of cisplatin resistance and potential for its clinical reversal. Pharmacotherapy. 1996 Jan-Feb;16(1):16–39. [PubMed]
  • Gundimeda U, Chen ZH, Gopalakrishna R. Tamoxifen modulates protein kinase C via oxidative stress in estrogen receptor-negative breast cancer cells. J Biol Chem. 1996 Jun 7;271(23):13504–13514. [PubMed]
  • Haldar S, Jena N, Croce CM. Inactivation of Bcl-2 by phosphorylation. Proc Natl Acad Sci U S A. 1995 May 9;92(10):4507–4511. [PMC free article] [PubMed]
  • Haldar S, Chintapalli J, Croce CM. Taxol induces bcl-2 phosphorylation and death of prostate cancer cells. Cancer Res. 1996 Mar 15;56(6):1253–1255. [PubMed]
  • Hockenbery DM, Oltvai ZN, Yin XM, Milliman CL, Korsmeyer SJ. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell. 1993 Oct 22;75(2):241–251. [PubMed]
  • Issandou M, Faucher C, Bayard F, Darbon JM. Opposite effects of tamoxifen on in vitro protein kinase C activity and endogenous protein phosphorylation in intact MCF-7 cells. Cancer Res. 1990 Sep 15;50(18):5845–5850. [PubMed]
  • Jaiyesimi IA, Buzdar AU, Decker DA, Hortobagyi GN. Use of tamoxifen for breast cancer: twenty-eight years later. J Clin Oncol. 1995 Feb;13(2):513–529. [PubMed]
  • Janssen YM, Barchowsky A, Treadwell M, Driscoll KE, Mossman BT. Asbestos induces nuclear factor kappa B (NF-kappa B) DNA-binding activity and NF-kappa B-dependent gene expression in tracheal epithelial cells. Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8458–8462. [PMC free article] [PubMed]
  • Kang Y, Perry RR. Modulatory effects of tamoxifen and recombinant human alpha-interferon on doxorubicin resistance. Cancer Res. 1993 Jul 1;53(13):3040–3045. [PubMed]
  • Kang Y, Cortina R, Perry RR. Role of c-myc in tamoxifen-induced apoptosis estrogen-independent breast cancer cells. J Natl Cancer Inst. 1996 Mar 6;88(5):279–284. [PubMed]
  • Kirk J, Houlbrook S, Stuart NS, Stratford IJ, Harris AL, Carmichael J. Differential modulation of doxorubicin toxicity to multidrug and intrinsically drug resistant cell lines by anti-oestrogens and their major metabolites. Br J Cancer. 1993 Jun;67(6):1189–1195. [PMC free article] [PubMed]
  • Leonessa F, Jacobson M, Boyle B, Lippman J, McGarvey M, Clarke R. Effect of tamoxifen on the multidrug-resistant phenotype in human breast cancer cells: isobologram, drug accumulation, and M(r) 170,000 glycoprotein (gp170) binding studies. Cancer Res. 1994 Jan 15;54(2):441–447. [PubMed]
  • Lopes MC, Vale MG, Carvalho AP. Ca2(+)-dependent binding of tamoxifen to calmodulin isolated from bovine brain. Cancer Res. 1990 May 1;50(9):2753–2758. [PubMed]
  • Los M, Dröge W, Stricker K, Baeuerle PA, Schulze-Osthoff K. Hydrogen peroxide as a potent activator of T lymphocyte functions. Eur J Immunol. 1995 Jan;25(1):159–165. [PubMed]
  • McClay EF, Albright KD, Jones JA, Christen RD, Howell SB. Tamoxifen modulation of cisplatin sensitivity in human malignant melanoma cells. Cancer Res. 1993 Apr 1;53(7):1571–1576. [PubMed]
  • McClay EF, Jones JA, Winski PJ, Albright KD, Christen RD, Howell SB. Determinants of tamoxifen sensitivity control the nature of the synergistic interaction between tamoxifen and cisplatin. Cancer Res. 1996 Sep 1;56(17):3993–3997. [PubMed]
  • Murrell GA, Francis MJ, Bromley L. Modulation of fibroblast proliferation by oxygen free radicals. Biochem J. 1990 Feb 1;265(3):659–665. [PMC free article] [PubMed]
  • Perry RR, Kang Y, Greaves B. Effects of tamoxifen on growth and apoptosis of estrogen-dependent and -independent human breast cancer cells. Ann Surg Oncol. 1995 May;2(3):238–245. [PubMed]
  • Poot M, Kavanagh TJ, Kang HC, Haugland RP, Rabinovitch PS. Flow cytometric analysis of cell cycle-dependent changes in cell thiol level by combining a new laser dye with Hoechst 33342. Cytometry. 1991;12(2):184–187. [PubMed]
  • Rao GN, Berk BC. Active oxygen species stimulate vascular smooth muscle cell growth and proto-oncogene expression. Circ Res. 1992 Mar;70(3):593–599. [PubMed]
  • Sen CK, Packer L. Antioxidant and redox regulation of gene transcription. FASEB J. 1996 May;10(7):709–720. [PubMed]
  • Wiseman H, Paganga G, Rice-Evans C, Halliwell B. Protective actions of tamoxifen and 4-hydroxytamoxifen against oxidative damage to human low-density lipoproteins: a mechanism accounting for the cardioprotective action of tamoxifen? Biochem J. 1993 Jun 15;292(Pt 3):635–638. [PMC free article] [PubMed]
  • Wiseman H, Laughton MJ, Arnstein HR, Cannon M, Halliwell B. The antioxidant action of tamoxifen and its metabolites. Inhibition of lipid peroxidation. FEBS Lett. 1990 Apr 24;263(2):192–194. [PubMed]
  • Ye Q, Bodell WJ. Production of 8-hydroxy-2'-deoxguanosine in DNA by microsomal activation of tamoxifen and 4-hydroxytamoxifen. Carcinogenesis. 1996 Aug;17(8):1747–1750. [PubMed]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Compound
    Compound
    PubChem Compound links
  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...