title: The Therapeutic Potential of AN-7, a Novel Histone Deacetylase Inhibitor, for Treatment of Mycosis Fungoides/Sezary Syndrome Alone or with Doxorubicin.
abstract: The 2 histone deacetylase inhibitors (HDACIs) approved for the treatment of cutaneous T-cell lymphoma (CTCL) including mycosis fungoides/sezary syndrome (MF/SS), suberoylanilide hydroxamic acid (SAHA) and romidepsin, are associated with low rates of overall response and high rates of adverse effects. Data regarding combination treatments with HDACIs is sparse. Butyroyloxymethyl diethylphosphate (AN-7) is a novel HDACI, which was found to have selective anticancer activity in several cell lines and animal models. The aim of this study was to compare the anticancer effects of AN-7 and SAHA, either alone or combined with doxorubicin, on MF/SS cell lines and peripheral blood lymphocytes (PBL) from patients with Sezary syndrome (SPBL). MyLa cells, Hut78 cells, SPBL, and PBL from healthy normal individuals (NPBL) were exposed to the test drugs, and the findings were analyzed by a viability assay, an apoptosis assay, and Western blot. AN-7 was more selectively toxic to MyLa cells, Hut78 cells, and SPBL (relative to NPBL) than SAHA and also acted more rapidly. Both drugs induced apoptosis in MF/SS cell lines, SAHA had a greater effect on MyLa cell line, while AN-7 induced greater apoptosis in SPBL; both caused an accumulation of acetylated histone H3, but AN-7 was associated with earlier kinetics; and both caused a downregulation of the HDAC1 protein in MF/SS cell lines. AN-7 acted synergistically with doxorubicin in both MF/SS cell lines and SPBL, and antagonistically with doxorubicin in NPBL. By contrast, SAHA acted antagonistically with doxorubicin on MF/SS cell lines, SPBL, and NPBL, leaving <50% viable cells. In conclusion, AN-7 holds promise as a therapeutic agent in MF/SS and has several advantages over SAHA. Our data provide a rationale for combining AN-7, but not SAHA, with doxorubicin to induce the cell death in MF/SS.
authors.affiliation: Laboratory for Molecular Dermatology, Felsenstein Medical Research Center, Petach Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Dermatology, Rabin Medical Center, Petach Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Lilach
authors.initials: L
authors.lastname: Moyal
authors.affiliation: Laboratory for Molecular Dermatology, Felsenstein Medical Research Center, Petach Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Nataly
authors.initials: N
authors.lastname: Feldbaum
authors.affiliation: Laboratory for Molecular Dermatology, Felsenstein Medical Research Center, Petach Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Neta
authors.initials: N
authors.lastname: Goldfeiz
authors.affiliation: Laboratory for Pharmacology and Experimental Oncology, Felsenstein Medical Research Center, Petach Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ada
authors.initials: A
authors.lastname: Rephaeli
authors.affiliation: Division of Medicinal Chemistry, Department of Chemistry, Bar Ilan University, Ramat Gan, Israel.
authors.forename: Abraham
authors.initials: A
authors.lastname: Nudelman
authors.affiliation: Division of Medicinal Chemistry, Department of Chemistry, Bar Ilan University, Ramat Gan, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Weitman
authors.affiliation: Laboratory for Pharmacology and Experimental Oncology, Felsenstein Medical Research Center, Petach Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Nataly
authors.initials: N
authors.lastname: Tarasenko
authors.affiliation: Laboratory for Molecular Dermatology, Felsenstein Medical Research Center, Petach Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Batia
authors.initials: B
authors.lastname: Gorovitz
authors.affiliation: Laboratory for Molecular Dermatology, Felsenstein Medical Research Center, Petach Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Leah
authors.initials: L
authors.lastname: Maron
authors.affiliation: Laboratory for Molecular Dermatology, Felsenstein Medical Research Center, Petach Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Shiran
authors.initials: S
authors.lastname: Yehezkel
authors.affiliation: Department of Dermatology, Rabin Medical Center, Petach Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Iris
authors.initials: I
authors.lastname: Amitay-Laish
authors.affiliation: Core Facility, Felsenstein Medical Research Center, Petach Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ido
authors.initials: I
authors.lastname: Lubin
authors.affiliation: Laboratory for Molecular Dermatology, Felsenstein Medical Research Center, Petach Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Dermatology, Rabin Medical Center, Petach Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Emmilia
authors.initials: E
authors.lastname: Hodak
mesh_terms: D000107:Acetylation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D002087:Butyrates; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D008214:Lymphocytes / Q000378:metabolism; D009182:Mycosis Fungoides / Q000188:drug therapy*; D010755:Organophosphates / Q000494:pharmacology / Q000627:therapeutic use*; D009943:Organophosphorus Compounds; D010710:Phosphates / Q000494:pharmacology / Q000627:therapeutic use*; D012751:Sezary Syndrome / Q000188:drug therapy*; D000077337:Vorinostat
chemical_list: D002087:Butyrates; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D010755:Organophosphates; D009943:Organophosphorus Compounds; D010710:Phosphates; C502471:diethoxyphosphoryloxymethyl butanoate; D000077337:Vorinostat; D004317:Doxorubicin; D006655:Histone Deacetylases