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2-Methoxyestradiol reverses doxorubicin resistance in human breast tumor xenograft

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Abstract

Purpose

2-Methoxyestradiol (2ME), an endogenous estradiol metabolite, was developed as a novel agent based on its antitumor activity and lack of toxicity. This study was designed to investigate the modulatory effect of 2ME on the antitumor effect of doxorubicin (Dox) in resistant breast tumor xenograft. Resistant MCF-7/Dox cells were implanted subcutaneously in nude mice

Methods

Treatment with Dox 5 mg/kg, 2ME 30 mg/kg and their combination continued twice a week for 2 weeks.

Results

Following 28 days from starting the treatment with Dox alone, the change in tumor volume from first day of treatment was 455.6 ± 16.2%. Combined Dox and 2ME treatment significantly reduced tumor volume to 20.8 ± 43%. Also, combined therapy resulted in enhanced tumor apoptotic and reduced proliferative activities relative to Dox alone. The apoptotic indices were 0.13 ± 0.03 and 0.75 ± 0.06 in Dox alone and Dox + 2ME groups, respectively. For Dox alone group, expression of the proliferative markers PCNA and Ki67 were 0.78 ± 0.06 and 0.63 ± 0.18, respectively. They were significantly reduced to 0.28 ± 0.1 and 0.12 ± 0.1 for their corresponding combined Dox and 2ME group. Interaction analysis clearly indicated that 2ME synergies antitumor, apoptotic and anti-proliferative activity of Dox. Examining body weight, hepatic and cardiac histopathology of the different treatment groups revealed no significant signs of toxicity.

Conclusion

These findings suggest that 2ME reverses Dox resistance, with benign side effects profile.

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References

  1. Chaudhary P, Roninson I (1993) Induction of multi-drug resistance in human cells by transient exposure to different chemotherapeutic drugs. J Natl Cancer Inst 85:632–639

    Article  PubMed  CAS  Google Scholar 

  2. Chauhan D, Catley L, Hideshima T, Li G, Leblanc R, Gupta D, Sattler M, Richardson P, Schlossman R, Podar K, Weller E, Munshi N, Anderson K (2002) 2-Methoxyestradiol overcomes drug resistance in multiple myeloma cells. Blood 100(6):2187–2194

    Article  PubMed  CAS  Google Scholar 

  3. Chen J, Konopleva M, Andreeff M, Multani A, Pathak S, Mehta K (2004) Drug-resistant breast carcinoma (MCF-7) cells are paradoxically sensitive to apoptosis. J Cell Physiol 200(2):223–234

    Article  PubMed  CAS  Google Scholar 

  4. D’Amato R, Lin C, Flynn E, Folkman J, Hamel E (1994) 2-Methoxyestradiol, an endogenous mammalian metabolite, inhibits tubulin polymerization by interacting at the colchicines site. Proc Natl Acad Sci USA 91:3964–3968

    Article  PubMed  CAS  Google Scholar 

  5. Dingli D, Timm M, Russell S, Witzing T, Rajkumar S (2002) Promising preclinical activity of 2-methoxyestradiol in multiple myeloma. Clin Cancer Res 8:3948–3954

    PubMed  CAS  Google Scholar 

  6. Dobos J, Tímár J, Bocsi J, Burián Z, Nagy K, Barna G, Peták I, Ladányi A (2004) In vitro and in vivo antitumor effect of 2-methoxyestradiol on human melanoma. Int J Cancer 112(5):771–776

    Article  PubMed  CAS  Google Scholar 

  7. Fostis T, Zhang Y, Pepper M, Adlercreutz H, Montesano R, Nawroth P, Schweigerer L (1994) The endogenous oestrogen metabolite 2-methoxyestradiol inhibits angiogenesis and suppresses tumour growth. Nature 368:237–239

    Article  Google Scholar 

  8. Han G, Liu Z, Shimoi K, Zhu B (2005) Synergism between the anticancer actions of 2-methoxyestradiol and microtubule-disrupting agents in human breast cancer. Cancer Res 65(2):387–393

    PubMed  CAS  Google Scholar 

  9. Herzog C, Tsokos M, Bates S, Fojo A (1993) Increased mdr-1/P-glycoprotein expression after treatment of human colon carcinoma cells with P-glycoprotein antagonists. J Biol Chem 268:2946–2952

    PubMed  CAS  Google Scholar 

  10. Ireson C, Chander S, Purohit A, Perera S, Newman S, Parish D, Leese M, Smith A, Potter B Reed M (2004) Pharmacokinetics and efficacy of 2-methoxyestradiol and 2-methoxoestradiol-bis-sulphamate in vivo in rodents. Br J Cancer 90:932–937

    Article  PubMed  CAS  Google Scholar 

  11. Ishida H, Okabe M, Gomi K, Horiuchi R, Mikami K, Naito M, Tsuruo T (1994) Modulation of adriamycin resistance in human breast carcinoma MCF-7 cells in vitro and in vivo by medroxyprogesterone acetate. Jpn J Cancer Res 85:542–549

    PubMed  CAS  Google Scholar 

  12. Kerb R, Hoffmeyer S, Brinkmann U (2001) ABC drug transporters: hereditary polymorphism and pharmacological impact in MDR1, MRP1 and MRP2. Pharmacogenomics 2:51–64

    Article  PubMed  CAS  Google Scholar 

  13. Klauber N, Parangi S, Flynn E, Hamel E, D’Amato R (1997) Inhibition of angiogenesis and breast cancer in mice by the microtubule inhibitors 2-methoxyestradiol and taxol. Cancer Res 57:81–86

    PubMed  CAS  Google Scholar 

  14. Leonard R, Rodger A, Dixon J (1994) Metastatic breast cancer. Br Med J 309:1501–1504

    CAS  Google Scholar 

  15. Li L, Da J, Landstrom M, Ulmsten U, Fu X (2005) Antiproliferative activity and toxicity of 2-methoxyestradiol in cervical cancer xenograft mice. Int J Gynecol Cancer 15:301–307

    Article  PubMed  CAS  Google Scholar 

  16. Ling V (1997) Multidrug resistance: molecular mechanisms and clinical relevance. Cancer Chemother Pharmacol 40(suppl):S3–S10

    Article  PubMed  CAS  Google Scholar 

  17. MacCarthy-Morrogh L, Townsend P, Purohit A, Hejaz H, Potter B, Reed M, Packham G (2000) Differentical effects of estrone and estrone-3-O-sulphamate derivatives on mitotic arrest, apoptosis and microtubule assembly in human breast cancer cells. Cancer Res 60:5441–5550

    PubMed  CAS  Google Scholar 

  18. McCormick D, Johnson W, Pribluda V, Green S, Tomaszewski J, Smith A (2000) Preclinical development of 2-methoxyestradiol (2ME2, NSC-659853). [Abstract]. Proc Am Assoc Cancer Res 41:328

    Google Scholar 

  19. Mimnaugh E, Faichild C, Fruehauf J, Sinha B (1991) Biochemical and pharmacological characterization of MCF-7 drug sensitive and Adr multidrug-resistant human breast tumor xenografts in athymic nude mice. Biochem Pharmacol 42:2, 391–402

    Article  Google Scholar 

  20. Mehta K (1994) High levels of transglutaminase expression in doxorubicin resistant human breast carcinoma cells. Int J Cancer 58:400–406

    Article  PubMed  CAS  Google Scholar 

  21. Merriam G, MacLusky N, Picard M, Naftolin F (1980) Comparative properties of the catechol estrogens, I: methylation by catechol-O-methyl-transferase and binding to cytosol estrogen receptors. Steroids 36:1–11

    Article  PubMed  CAS  Google Scholar 

  22. Mooberry S (2003) New insights into 2-methoxyestradio, a promising antiangiogenic and antitumor agent. Curr Opin Oncol 15:425–430

    Article  PubMed  CAS  Google Scholar 

  23. Mueck A, Seeger H, Huober J (2004) Chemotherapy of breast cancer-additive anticancerogenic effects by 2-methoxyestradiol? Life Sci 75(10):1205–1210

    Article  PubMed  CAS  Google Scholar 

  24. O’Connor R (2007) The pharmacology of cancer resistance. Anticancer Res 27(3A):1267–1272

    PubMed  CAS  Google Scholar 

  25. Pribluda V, LaVallee T, Green S (2002) 2-Methoxyestradiol: a novel endogenous chemotherapeutic and anti-angiogenic agent. In: Fan T-PD, Kohn E (eds) The new angiotherapy. Humana Press, Totawa, pp 387–408

    Google Scholar 

  26. Ryschich E, Werner J, Gebhard M, Klar E, Schmidt J (2003) Angiogenesis inhibition with TNP-470, 2-methoxyestradil, and paclitaxel in experimental pancreatic carcinoma. Pancreas 26:166–172

    Article  PubMed  CAS  Google Scholar 

  27. Sutherland T, Schuliga M, Harris T, Eckhardt B, Anderson R, Quan L, Stewart A (2005) 2-Methoxyestradiol is an estrogen receptor agonist that supports tumor growth in murine xenograft models of breast cancer. Clinical Cancer Res 11:1722–1732

    Article  CAS  Google Scholar 

  28. Tinley T, Leal R, Randall-Hlubek D, Cessac J, Wilkens L, Rao P, Mooberry S (2003) Novel 2-methoxyestradiol analogues with antitumor activity. Cancer Res 63:1538–1549

    PubMed  CAS  Google Scholar 

  29. Ulmann C, Eliot H, Sinha B (1991) Distibution, DNA damage and cytotoxic effects of etoposide in human tumor xenografts in vivo. Anticancer Res 11:1379–1382

    Google Scholar 

  30. Vijayanathan V, Venkiteswaran S, Nair S, Verma A, Thomas T, Zhu B, Thomas T (2006) Physiologic levels of 2-methoxyestradiol interfere with nongenomic signaling of 17beta-estradiol in human breast cancer cells. Clin Cancer Res 12(7 Pt 1):2038–2048

    Article  PubMed  CAS  Google Scholar 

  31. Wang L, Yang C, Horwitz S, Trail P, Casazza A (1994) Reversal of the human and murine multidrug-resistance phenotype with megestrol acetate. Cancer Chemother Pharmacol 34:96–102

    Article  PubMed  CAS  Google Scholar 

  32. Wild R, Ramakrishnan S, Sedgewick J, Griffioen A (2000) Quantitative assessment of angiogenesis and tumor vessel architecture by computer-assisted digital image analysis: effects of VEGF–toxin conjugate on tumor microvessel density. Microvasc Res 59:368–376

    Article  PubMed  CAS  Google Scholar 

  33. Von Hoff D, Rozencweig M, Piccat M (1982) The cardiotoxicity of anticancer agents. Semin Oncol 9:23–33

    Google Scholar 

  34. Yi X, Bekeredjian R, DeFilippis N, Siddiquee Z, Fernandez E, Shohet R (2006) Transcriptional analysis of doxorubicin-induced cardiotoxicity. Am J Physiol Heart Circ Physiol 290(3):H1098–102

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was funded mainly by the Egyptian interior mission department, Ministry of Higher Education, Egypt.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, University of Texas-Medical Branch, Galveston, TX, USA

    Samar S. Azab, Salama A. Salama, Memy H. Hassan & Hala Fouad

  2. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt

    Samar S. Azab, Amani E. Khalifa & Ebtehal El-Demerdash

  3. Nashville General Hospital at Meharry, Nashville, TN, USA

    Ayman Al-Hendy

  4. Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, 21589, Saudi Arabia

    Ashraf B. Abdel-Naim

Authors
  1. Samar S. Azab
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  2. Salama A. Salama
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Correspondence to Ashraf B. Abdel-Naim.

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Azab, S.S., Salama, S.A., Hassan, M.H. et al. 2-Methoxyestradiol reverses doxorubicin resistance in human breast tumor xenograft. Cancer Chemother Pharmacol 62, 893–902 (2008). https://doi.org/10.1007/s00280-008-0679-9

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  • DOI: https://doi.org/10.1007/s00280-008-0679-9

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