Histone deacetylase inhibitors (HDACi) are compounds that target the epigenome and cause
tumor cell-selective apoptosis. A large number of these agents that have different chemical structures and can target multiple HDACs are being testing in clinical trials and
vorinostat is now an approved
drug for the treatment of
cutaneous T-cell lymphoma. Although these agents are showing promise for the treatment of
hematologic malignancies, it is possible that different drugs may have different mechanistic,
biological, and therapeutic activities. When comparing an HDACi belonging to the
hydroxamic acid class of compounds (
vorinostat) with a cyclic tetrapeptide (
romidepsin), we showed that these agents regulate the expression of a common set of cellular genes, but certain genes specifically responded to each agent. Using the Emu-myc mouse model of
B-cell lymphoma, we showed previously that overexpression of the prosurvival
proteins Bcl-2 and Bcl-XL inhibited the apoptotic and therapeutic activities of the
vorinostat. Herein, we compared and contrasted the apoptotic-inducing activities of the
hydroxamic acid oxamflatin with
romidepsin. Like
vorinostat,
oxamflatin was unable to kill
lymphomas overexpressing Bcl-2 and Bcl-XL, indicating that these
proteins can generally protect cells against this class of HDACi. In contrast,
romidepsin was able to induce apoptosis in
lymphomas overexpressing Bcl-2 with delayed kinetics of cell death and could mediate therapeutic responses against these
lymphomas. However,
romidepsin was inactive when Bcl-XL was overexpressed. These data provide strong support that HDACi of different chemical classes may have subtle yet potentially important differences in their molecular and
biological activities.