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Histone deacetylase inhibitors: the anticancer, antimetastatic and antiangiogenic activities of AN-7 are superior to those of the clinically tested AN-9 (Pivanex)

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Abstract

Histone deacetylase inhibitory prodrugs that are metabolized to butyric acid and formaldehyde possess antineoplastic properties and low toxicity. We sought to characterize the antiangiogenic and antimetastatic activities of two lead prodrugs, pivaloyloxymethyl butyrate (AN-9) and butyroyloxymethyl-diethyl phosphate (AN-7) in murine cancer models. In the sc implanted human colon carcinoma HT-29 xenograft model AN-7, exhibited superior anticancer activity compared to AN-9, as was evident by the significantly greater inhibition of tumor growth and reduction of serum CEA. AN-7 was also more effective in reducing mean vessel density (MVD) by 7-fold, bFGF, Ki-67 (7-fold) and HIF-1α in immunohistochemically stained tumor sections. Semi-quantitative evaluation of the levels of bFGF, HDAC1 and HIF-1α by Western blot analysis showed a decrease in expression only in the tumors of mice treated with AN-7. The level of bFGF was reduced 3-fold in the tumor and that of TIMP1 was elevated (by 3-fold) in the serum of AN-7 treated mice. In a 4T1 metastatic breast carcinoma model, AN-7 inhibited the formation of lung lesions by 76% and AN-9 by 47%, further demonstrating the greater efficacy of AN-7 compared to AN-9 (P < 0.02). Both AN-7 and AN-9 exhibited antimetastatic and antiangiogenic activities by reducing vascularization, bFGF expression and HIF-1α. Yet, AN-7 was more potent than AN-9.

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Abbreviations

bFGF:

Basic fibroblast grows factor

BA:

Butyric acid

CEA:

Carcinoembryonic antigen

DAB:

Diaminobenzidine

HDAC:

Histone deacetylase

HDACI:

Histone deacetylase inhibitors

Hif-1α:

Hypoxia inducible factor alpha

IHC:

Immunohistochemistry

MDV:

Mean vessel density

MMP:

Matrix metalloproteinase

PSA:

Prostate specific antigen

PTEN:

Phosphatase and tensin homolog

TIMP 1:

Tissue inhibitor of metalloproteinases-1

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Acknowledgements

We thank Ms. S. Dominitz for assistance in editing the manuscript. This work was supported in part by grants from: Ministry of Commerce and Industry and Teva Pharmaceutical Industry Ltd (A.N. and A.R.); The Marcus Center for Pharmaceutical and Medicinal Chemistry at Bar Ilan University (A.N.); Fellowships from the Ministry of Absorption in Science (I. T. and N.T.). Nataly Tarasenko carried out this work as part of the requirements for a PhD degree from the Department of Human Genetics and Molecular Biology, Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.

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Authors and Affiliations

  1. Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Beilinson Campus, Petach Tikva, 49100, Israel

    Nataly Tarasenko, Igor Tarasenko, Aida Inbal & Ada Rephaeli

  2. Department of Human Genetics and Molecular Biology, Sackler Medical School, Tel Aviv University, Tel Aviv, Israel

    Nataly Tarasenko

  3. Chemistry Department, Bar-Ilan University, Ramat Gan, 52900, Israel

    Abraham Nudelman

  4. Department of Radiation Oncology and Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, 94143, USA

    Michal Entin-Meer & Daphne Hass-Kogan

  5. Thrombosis and Haemostasis Unit, Beilinson Hospital, Rabin Medical Centre, Petah Tikva, Israel

    Aida Inbal

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  1. Nataly Tarasenko
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Correspondence to Ada Rephaeli.

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Tarasenko, N., Nudelman, A., Tarasenko, I. et al. Histone deacetylase inhibitors: the anticancer, antimetastatic and antiangiogenic activities of AN-7 are superior to those of the clinically tested AN-9 (Pivanex). Clin Exp Metastasis 25, 703–716 (2008). https://doi.org/10.1007/s10585-008-9179-x

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