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. 1999 Jan;79(2):257–263. doi: 10.1038/sj.bjc.6690042

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

C Ferlini 1, G Scambia 1, M Marone 1, M Distefano 1, C Gaggini 1, G Ferrandina 1, A Fattorossi 1, G Isola 1, P Benedetti Panici 1, S Mancuso 1
PMCID: PMC2362195  PMID: 9888466

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

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Selected References

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  1. Bass D. A., Parce J. W., Dechatelet L. R., Szejda P., Seeds M. C., 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] [Google Scholar]
  2. 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] [Google Scholar]
  3. Couldwell W. T., Hinton D. R., He S., Chen T. C., Sebat I., Weiss M. H., Law R. E. Protein kinase C inhibitors induce apoptosis in human malignant glioma cell lines. FEBS Lett. 1994 May 23;345(1):43–46. doi: 10.1016/0014-5793(94)00415-3. [DOI] [PubMed] [Google Scholar]
  4. 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. doi: 10.1002/(SICI)1097-0215(19961104)68:3<340::AID-IJC12>3.0.CO;2-C. [DOI] [PubMed] [Google Scholar]
  5. 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. doi: 10.1111/j.1365-2184.1996.tb00985.x. [DOI] [PubMed] [Google Scholar]
  6. 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. doi: 10.1038/bjc.1997.156. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. 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] [Google Scholar]
  8. Gundimeda U., Chen Z. H., 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. doi: 10.1074/jbc.271.23.13504. [DOI] [PubMed] [Google Scholar]
  9. Haldar S., Chintapalli J., Croce C. M. Taxol induces bcl-2 phosphorylation and death of prostate cancer cells. Cancer Res. 1996 Mar 15;56(6):1253–1255. [PubMed] [Google Scholar]
  10. Haldar S., Jena N., Croce C. M. Inactivation of Bcl-2 by phosphorylation. Proc Natl Acad Sci U S A. 1995 May 9;92(10):4507–4511. doi: 10.1073/pnas.92.10.4507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hockenbery D. M., Oltvai Z. N., Yin X. M., Milliman C. L., Korsmeyer S. J. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell. 1993 Oct 22;75(2):241–251. doi: 10.1016/0092-8674(93)80066-n. [DOI] [PubMed] [Google Scholar]
  12. Issandou M., Faucher C., Bayard F., Darbon J. M. 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] [Google Scholar]
  13. Jaiyesimi I. A., Buzdar A. U., Decker D. A., Hortobagyi G. N. Use of tamoxifen for breast cancer: twenty-eight years later. J Clin Oncol. 1995 Feb;13(2):513–529. doi: 10.1200/JCO.1995.13.2.513. [DOI] [PubMed] [Google Scholar]
  14. Janssen Y. M., Barchowsky A., Treadwell M., Driscoll K. E., Mossman B. T. 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. doi: 10.1073/pnas.92.18.8458. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kang Y., Cortina R., Perry R. R. Role of c-myc in tamoxifen-induced apoptosis estrogen-independent breast cancer cells. J Natl Cancer Inst. 1996 Mar 6;88(5):279–284. doi: 10.1093/jnci/88.5.279. [DOI] [PubMed] [Google Scholar]
  16. Kang Y., Perry R. R. Modulatory effects of tamoxifen and recombinant human alpha-interferon on doxorubicin resistance. Cancer Res. 1993 Jul 1;53(13):3040–3045. [PubMed] [Google Scholar]
  17. Kirk J., Houlbrook S., Stuart N. S., Stratford I. J., Harris A. L., 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. doi: 10.1038/bjc.1993.224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. 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] [Google Scholar]
  19. Lopes M. C., Vale M. G., Carvalho A. P. Ca2(+)-dependent binding of tamoxifen to calmodulin isolated from bovine brain. Cancer Res. 1990 May 1;50(9):2753–2758. [PubMed] [Google Scholar]
  20. Los M., Dröge W., Stricker K., Baeuerle P. A., Schulze-Osthoff K. Hydrogen peroxide as a potent activator of T lymphocyte functions. Eur J Immunol. 1995 Jan;25(1):159–165. doi: 10.1002/eji.1830250127. [DOI] [PubMed] [Google Scholar]
  21. McClay E. F., Albright K. D., Jones J. A., Christen R. D., Howell S. B. Tamoxifen modulation of cisplatin sensitivity in human malignant melanoma cells. Cancer Res. 1993 Apr 1;53(7):1571–1576. [PubMed] [Google Scholar]
  22. McClay E. F., Jones J. A., Winski P. J., Albright K. D., Christen R. D., Howell S. B. 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] [Google Scholar]
  23. Murrell G. A., Francis M. J., Bromley L. Modulation of fibroblast proliferation by oxygen free radicals. Biochem J. 1990 Feb 1;265(3):659–665. doi: 10.1042/bj2650659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Perry R. R., 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. doi: 10.1007/BF02307030. [DOI] [PubMed] [Google Scholar]
  25. Poot M., Kavanagh T. J., Kang H. C., Haugland R. P., Rabinovitch P. S. 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. doi: 10.1002/cyto.990120214. [DOI] [PubMed] [Google Scholar]
  26. Rao G. N., Berk B. C. Active oxygen species stimulate vascular smooth muscle cell growth and proto-oncogene expression. Circ Res. 1992 Mar;70(3):593–599. doi: 10.1161/01.res.70.3.593. [DOI] [PubMed] [Google Scholar]
  27. Sen C. K., Packer L. Antioxidant and redox regulation of gene transcription. FASEB J. 1996 May;10(7):709–720. doi: 10.1096/fasebj.10.7.8635688. [DOI] [PubMed] [Google Scholar]
  28. Wiseman H., Laughton M. J., Arnstein H. R., 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. doi: 10.1016/0014-5793(90)81371-t. [DOI] [PubMed] [Google Scholar]
  29. 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. doi: 10.1042/bj2920635. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Ye Q., Bodell W. J. Production of 8-hydroxy-2'-deoxguanosine in DNA by microsomal activation of tamoxifen and 4-hydroxytamoxifen. Carcinogenesis. 1996 Aug;17(8):1747–1750. doi: 10.1093/carcin/17.8.1747. [DOI] [PubMed] [Google Scholar]

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