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.