Advertisement

LHRH Receptor Targeted Therapy for Breast Cancer

  • S.S. Kakar
  • H. Jin
  • B. Hong
  • J.W. Eaton
  • Kyung A. Kang
Part of the Advances In Experimental Medicine And Biology book series (AEMB, volume 614)

Abstract

Breast cancer remains the most common cancer among women, with an estimated 212,920 new cases and 40,970 deaths in the United States in 2006. The present work extends the studies of nanoparticles targeted to the luteinizing hormone-releasing hormone (LHRH) receptor which is overexpressed in breast, ovarian, endometrial and prostate cancer cells. In contrast, LHRH receptors are not expressed, or expressed at a low level in most visceral organs. In our studies, we conjugated Fe3O4 nanoparticles (20–30 nm) with [D-Trp6]LHRH (Triptorelin), a decapeptide analog of LHRH currently used for treatment of sex-hormone-dependent tumors. Conjugation of [D-Trp6]LHRH to Fe3O4 particles retained its binding affinity and biological activity for the LHRH receptor. Treatment of two separate breast tumor cell lines (MCF-7 and MDA-MB231) with these conjugated nanoparticles resulted in 95–98% cell death and loss of viability within 24 h whereas no change in cell proliferation or cell apoptosis was observed in cells treated with equal amounts of either [D-Trp6]LHRH or unconjugated Fe3O4 nanoparticles. These studies provide critical and important information regarding use of LHRH receptor targeted therapy for breast cancer.

Keywords

Magnetite Nanoparticles Breast Tumor Cell Magnetite Particle LHRH Analog LbT2 Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    A. Jemal, R. Siegel, E. Ward et al. Cancer statistics, 2006. CA: a Cancer J Clin 2006; 56(2): 106–130CrossRefGoogle Scholar
  2. 2.
    A.M. Bajo, A.V. Schally, G, Halmos et al. Targeted doxorubicin containing luteinizing hormone-releasing hormone analogue AN-152 inhibits the growth of doxorubicin-resistant MX-1 human breast cancers. Clin Cancer Res 2003; 9: 3742–3748PubMedGoogle Scholar
  3. 3.
    S.S. Kakar, M.T. Malik, S.J. Winters et al. Gonadotropin-releasing hormone receptors: structure, expression, and signaling transduction. Vit Horm 2004; 69: 151–207Google Scholar
  4. 4.
    A. Nagy, A.V. Schally. Targeting of cytotoxic luteinizing hormone-releasing hormone analogs to breast, ovarian, endometrial, and prostate cancers. Biol Reprod 2005; 73(5): 851–859PubMedCrossRefGoogle Scholar
  5. 5.
    S.S. Dharap, Y. Wang, P. Chandna et al. Tumor-specific targeting of an anticancer drug delivery system by LHRH peptide. Proc Nat Acad Sci USA 2005; 102(36): 12962–12967PubMedCrossRefGoogle Scholar
  6. 6.
    J. Zhou, C. Leuschner, C. Kumar et al. Sub-cellular accumulation of magnetic nanoparticles in breast tumors and metastases. Biomaterials 2006; 27(9): 2001–2008PubMedCrossRefGoogle Scholar
  7. 7.
    C. Leuschner, C. Kumar, M. Urbina et al. The use of ligand conjugated supermagnetic iron oxide nanoparticles (SPION) for early detection of metastasis. In INST Naotech Tech Proc 1005; 1: 5–6Google Scholar
  8. 8.
    M. Islam, L. Fu, M. Su et al. Novel one-step synthesis of amine-stabilized aqueous colloidal gold nanoparticles. J Material Chem 2004; 14; 1795–1797CrossRefGoogle Scholar
  9. 9.
    S.S. Kakar, L.C. Musgrove, D.C. Dever et al. Cloning, sequencing, and expression of human gonadotropin-releasing hormone (GnRH) receptor, Biochem Biophys Res Commun 1992; 189: 289–295PubMedCrossRefGoogle Scholar
  10. 10.
    10. S.S. Kakar, S.J. Winters, W. Zacharias et al. Identification of distinct gene expression profiles associated with treatment of LbetaT2 cells with gonadotropin-releasing hormone agonist using microarray analysis. Gene 2003; 308: 67–77Google Scholar
  11. 11.
    P. Thomas, P.L. Mellon, J. Turgeon et al. The L beta T2 clonal gonadotrope: a model for single cell studies of endocrine cell secretion. Endocrinology 1996; 137: 2979–2989PubMedCrossRefGoogle Scholar
  12. 12.
    G.Y. Bedecarrats, K.D. Linher, J.A. Janovick et al. Four naturally occurring mutations in the human GnRH receptor affect ligand binding and receptor function. Mol Cell Endocrin 2003; 205(1–2), 51–64CrossRefGoogle Scholar
  13. 13.
    A. Mangia, S. Tommasi, S.J. Reshkin et al. Gonadotropin releasing hormone receptor expression in primary breast cancer: comparison of imunohistochemical, radioligand and Western blot analyses, Oncol Rep 2002; 9(5): 1127–1132PubMedGoogle Scholar
  14. 14.
    T. Moriya, T. Suzuki, M. Pilichowska et al. Immunohistochemical expression of gonadotropin releasing hormone receptor in human breast carcinoma. Pathol Int 2001; 51(5): 333–337PubMedCrossRefGoogle Scholar
  15. 15.
    M. W. Qian, J.W. Eaton. Iron translocation by free fatty acids, Am J Path 1991; 139(6): 1425–1434PubMedGoogle Scholar
  16. 16.
    S.S. Kakar. Inhibition of growth and proliferation of EcRG293 cell line expressing high-affinity Gonadotropin-releasing hormone (GnRH) receptor under the control of an inducible promoter by GnRH agonist (D-Lys6)GnRH and antagonist (Antide). Cancer Res 1998; 58(20): 4558–4560PubMedGoogle Scholar
  17. 17.
    Z. Yu, H.L. Persson, J.W. Eaton et al. Intralysosomal iron: a major determinant of oxidant-induced cell death. Free Rad Biol Med 2003; 34(10): 1243–1252PubMedCrossRefGoogle Scholar
  18. 18.
    H.L. Persson, Z. Yu, O. Tirosh et al. Prevention of oxidant-induced cell death by lysosomotropic iron chelators. Free Rad Biol Med 2004; 34(10): 1295–1305CrossRefGoogle Scholar
  19. 19.
    U.T. Brunk, J. Neuzil, J.W. Eaton. Lysosomal involvement in apoptosis, Redox Rep 2001;6(2): 91–97PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • S.S. Kakar
    • 1
  • H. Jin
    • 2
  • B. Hong
    • 2
  • J.W. Eaton
    • 1
  • Kyung A. Kang
    • 2
  1. 1.Department of Medicine and James Graham Brown Cancer CenterUniversity of LouisvilleLouisville
  2. 2.Department of Chemical Engineering, J.B Speed School of EngineeringUniversity of LouisvilleLouisville

Personalised recommendations