Combination of methylselenocysteine with tamoxifen inhibits MCF-7 breast cancer xenografts in nude mice through elevated apoptosis and reduced angiogenesis

  • Zengshan Li
  • Latonya Carrier
  • Aditi Belame
  • Arunthavarani Thiyagarajah
  • Virgilio A. Salvo
  • Matthew E. Burow
  • Brian G. Rowan
Preclinical Study

Abstract

To investigate the therapeutic effect of methylselenocysteine (MSC) combined with tamoxifen in MCF-7 breast cancer xenograft and the underlying mechanisms. MCF-7 breast cancer xenograft was established in ovariectomized female athymic nude mice and treated with tamoxifen and/or MSC. Tumor size was measured twice a week. Immunohistochemistry and TUNEL assays were used to measure ERα expression, ERα target genes (progesterone receptor (PR) and cyclin D1 expression), Ki-67 index, apoptosis and microvessel density. Combined treatment with tamoxifen and MSC synergistically inhibited tumor growth compared to MSC alone and tamoxifen alone. MSC alone or MSC + tamoxifen significantly reduced ERα, PR and cyclin D1, Ki67 index and microvessel density while increasing apoptosis in tumor tissues. These findings demonstrate synergistic growth inhibition of ERα positive breast cancer xenografts by combination of tamoxifen with organic selenium compounds. Organic selenium may provide added benefit when combined with tamoxifen in adjuvant therapy or prevention.

Keywords

Breast cancer Xenograft Synergy Selenium Tamoxifen Apoptosis Proliferation Angiogenesis 

Abbreviations

MSC

Methylselenocysteine

ERα

Estrogen receptor α

PR

Progesterone receptor

TAM

Tamoxifen

MVD

Microvessel density

E2

Estradiol

AR

Androgen receptor

PSA

Prostate specific antigen

PARP

Poly ADP-ribose polymerase

TUNEL

Terminal DNA transferase-mediated dUTP nick end labeling

Notes

Acknowledgment

This project was supported, in part, by grants from the Louisiana Cancer Research Consortium to BGR.

References

  1. 1.
    Dong Y, Ganther HE, Stewart C et al (2002) Identification of molecular targets associated with selenium-induced growth inhibition in human breast cells using cDNA microarrays. Cancer Res 62:708–714PubMedGoogle Scholar
  2. 2.
    Wang Z, Jiang C, Lu J (2002) Induction of caspase-mediated apoptosis and cell-cycle G1 arrest by selenium metabolite methylselenol. Mol Carcinog 34:113–120. doi: 10.1002/mc.10056 CrossRefPubMedGoogle Scholar
  3. 3.
    Sinha R, Medina D (1997) Inhibition of cdk2 kinase activity by methylselenocysteine in synchronized mouse mammary epithelial tumor cells. Carcinogenesis 18:1541–1547. doi: 10.1093/carcin/18.8.1541 CrossRefPubMedGoogle Scholar
  4. 4.
    Ip C, Zhu Z, Thompson HJ et al (1999) Chemoprevention of mammary cancer with Se-allylselenocysteine and other selenoamino acids in the rat. Anticancer Res 19:2875–2880PubMedGoogle Scholar
  5. 5.
    Ip C (1998) Lessons from basic research in selenium and cancer prevention. J Nutr 128:1845–1854PubMedGoogle Scholar
  6. 6.
    Clark LC, Combs GF Jr, Turnbull BW et al (1996) Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional prevention of cancer study group. JAMA 276:1957–1963. doi: 10.1001/jama.276.24.1957 CrossRefPubMedGoogle Scholar
  7. 7.
    Cao S, Durrani FA, Rustum YM (2004) Selective modulation of the therapeutic efficacy of anticancer drugs by selenium containing compounds against human tumor xenografts. Clin Cancer Res 10:2561–2569. doi: 10.1158/1078-0432.CCR-03-0268 CrossRefPubMedGoogle Scholar
  8. 8.
    Ip C, Dong Y (2001) Methylselenocysteine modulates proliferation and apoptosis biomarkers in premalignant lesions of the rat mammary gland. Anticancer Res 21:863–867PubMedGoogle Scholar
  9. 9.
    Lu J, Jiang C, Kaeck M et al (1995) Dissociation of the genotoxic and growth inhibitory effects of selenium. Biochem Pharmacol 50:213–219. doi: 10.1016/0006-2952(95)00119-K CrossRefPubMedGoogle Scholar
  10. 10.
    Dong Y, Zhang H, Hawthorn L et al (2003) Delineation of the molecular basis for selenium-induced growth arrest in human prostate cancer cells by oligonucleotide array. Cancer Res 63:52–59PubMedGoogle Scholar
  11. 11.
    Li S, Zhou Y, Wang R et al (2007) Selenium sensitizes MCF-7 breast cancer cells to doxorubicin-induced apoptosis through modulation of phospho-Akt and its downstream substrates. Mol Cancer Ther 6:1031–1038. doi: 10.1158/1535-7163.MCT-06-0643 CrossRefPubMedGoogle Scholar
  12. 12.
    Lee SO, Yeon Chun J, Nadiminty N et al (2006) Monomethylated selenium inhibits growth of LNCaP human prostate cancer xenograft accompanied by a decrease in the expression of androgen receptor and prostate-specific antigen (PSA). Prostate 66:1070–1075. doi: 10.1002/pros.20329 CrossRefPubMedGoogle Scholar
  13. 13.
    Bhattacharya A, Seshadri M, Oven SD et al (2008) Tumor vascular maturation and improved drug delivery induced by methylselenocysteine leads to therapeutic synergy with anticancer drugs. Clin Cancer Res 14:3926–3932. doi: 10.1158/1078-0432.CCR-08-0212 CrossRefPubMedGoogle Scholar
  14. 14.
    Love RR (1989) Tamoxifen therapy in primary breast cancer: biology, efficacy, and side effects. J Clin Oncol 7:803–815PubMedGoogle Scholar
  15. 15.
    Jordan VC (1992) The strategic use of antiestrogens to control the development and growth of breast cancer. Cancer 70:977–982PubMedGoogle Scholar
  16. 16.
    Fisher B, Costantino JP, Wickerham DL et al (1998) Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:1371–1388. doi: 10.1093/jnci/90.18.1371 CrossRefPubMedGoogle Scholar
  17. 17.
    Fornander T, Rutqvist LE, Cedermark B et al (1989) Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1:117–120. doi: 10.1016/S0140-6736(89)91141-0 CrossRefPubMedGoogle Scholar
  18. 18.
    Johnston SR, Dowsett M, Smith IE (1992) Towards a molecular basis for tamoxifen resistance in breast cancer. Ann Oncol 3:503–511PubMedGoogle Scholar
  19. 19.
    Osborne CK (1998) Tamoxifen in the treatment of breast cancer. N Engl J Med 339:1609–1618. doi: 10.1056/NEJM199811263392207 CrossRefPubMedGoogle Scholar
  20. 20.
    Li Z, Carrier L, Rowan BG (2008) Methylseleninic acid synergizes with tamoxifen to induce caspase-mediated apoptosis in breast cancer cells. Mol Cancer Ther 7:3056–3063. doi: 10.1158/1535-7163.MCT-07-2142 CrossRefPubMedGoogle Scholar
  21. 21.
    Shah YM, Kaul A, Dong Y et al (2005) Attenuation of estrogen receptor alpha (ERalpha) signaling by selenium in breast cancer cells via downregulation of ERalpha gene expression. Breast Cancer Res Treat 92:239–250. doi: 10.1007/s10549-005-3203-5 CrossRefPubMedGoogle Scholar
  22. 22.
    Salvo VA, Boue SM, Fonseca JP et al (2006) Antiestrogenic glyceollins suppress human breast and ovarian carcinoma tumorigenesis. Clin Cancer Res 12:7159–7164. doi: 10.1158/1078-0432.CCR-06-1426 CrossRefPubMedGoogle Scholar
  23. 23.
    Hansen S, Grabau DA, Rose C et al (1998) Angiogenesis in breast cancer: a comparative study of the observer variability of methods for determining microvessel density. Lab Invest 78:1563–1573PubMedGoogle Scholar
  24. 24.
    Shah YM, Al Dhaheri M, Dong Y et al (2005) Selenium disrupts estrogen receptor (alpha) signaling and potentiates tamoxifen antagonism in endometrial cancer cells and tamoxifen-resistant breast cancer cells. Mol Cancer Ther 4:1239–1249. doi: 10.1158/1535-7163.MCT-05-0046 CrossRefPubMedGoogle Scholar
  25. 25.
    Hui R, Cornish AL, McClelland RA et al (1996) Cyclin D1 and estrogen receptor messenger RNA levels are positively correlated in primary breast cancer. Clin Cancer Res 2:923–928PubMedGoogle Scholar
  26. 26.
    Moy B, Goss PE (2006) Estrogen receptor pathway: resistance to endocrine therapy and new therapeutic approaches. Clin Cancer Res 12:4790–4793. doi: 10.1158/1078-0432.CCR-06-1535 CrossRefPubMedGoogle Scholar
  27. 27.
    Jiang C, Jiang W, Ip C et al (1999) Selenium-induced inhibition of angiogenesis in mammary cancer at chemopreventive levels of intake. Mol Carcinog 26:213–225. doi:10.1002/(SICI)1098-2744(199912)26:4<213::AID-MC1>3.0.CO;2-ZGoogle Scholar
  28. 28.
    Jiang C, Kim KH, Wang Z et al (2004) Methyl selenium-induced vascular endothelial apoptosis is executed by caspases and principally mediated by p38 MAPK pathway. Nutr Cancer 49:174–183. doi: 10.1207/s15327914nc4902_9 CrossRefPubMedGoogle Scholar
  29. 29.
    Wang Z, Hu H, Li G et al (2008) Methylseleninic acid inhibits microvascular endothelial cell cycle progression and decreases tumor microvessel density. Int J Cancer 122:15–24. doi: 10.1002/ijc.23077 CrossRefPubMedGoogle Scholar
  30. 30.
    Rustum Y, Cao S, Durrani F et al (2004) Se-(methyl)selenocysteine (MSC) potentiates the antitumor activity of irinotecan against human tumor xenografts and protects against drug induced toxicity. J Clin Oncol 22:2068 (meeting abstracts)Google Scholar
  31. 31.
    Fakih MG, Pendyala L, Brady W et al (2008) A phase I and pharmacokinetic study of selenomethionine in combination with a fixed dose of irinotecan in solid tumors. Cancer Chemother Pharmacol 62:499–508. doi: 10.1007/s00280-007-0631-4 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Zengshan Li
    • 1
    • 2
  • Latonya Carrier
    • 1
  • Aditi Belame
    • 1
  • Arunthavarani Thiyagarajah
    • 3
  • Virgilio A. Salvo
    • 4
  • Matthew E. Burow
    • 4
  • Brian G. Rowan
    • 1
  1. 1.Department of Structural & Cellular BiologyTulane University School of MedicineNew OrleansUSA
  2. 2.State Key Laboratory of Cancer Biology, Department of Pathology, XiJing HospitalFourth Military Medical UniversityXi’anPeople’s Republic of China
  3. 3.Department of Environmental Health Sciences, School of Public Health and Tropical MedicineTulane University Health Science CenterNew OrleansUSA
  4. 4.Section of Hematology & Medical Oncology, Department of MedicineTulane University School of MedicineNew OrleansUSA

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