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

Nataly Tarasenko, Abraham Nudelman, Igor Tarasenko, Michal Entin-Meer, Daphne Hass-Kogan, Aida Inbal, Ada Rephaeli*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)703-716
Number of pages14
JournalClinical and Experimental Metastasis
Volume25
Issue number7
DOIs
StatePublished - Nov 2008

Funding

FundersFunder number
Marcus Center for Pharmaceutical and Medicinal Chemistry at Bar Ilan University
Ministry of Absorption in Science
Ministry of commerce and industry and Teva Pharmaceutical Industry Ltd

    Keywords

    • 4T1 Breast cancer
    • AN-7
    • AN-9
    • Angiogenesis
    • HDAC inhibition
    • HT-29
    • Lung metastases
    • Prodrugs
    • Prostate carcinoma

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