Malignant
rhabdoid tumors (MRT) exhibit a very poor prognosis because of their resistance to chemotherapeutic agents and new
therapies are needed for the treatment of this
cancer. Here, we show that the
histone deacetylase (
HDAC) inhibitor FK228 (
depsipeptide) has an antitumor effect on MRT cells both in vitro and in vivo.
FK228 is a unique
cyclic peptide and is among the most potent inhibitors of both Class I and Class II HDACs.
FK228 inhibited proliferation and induced apoptosis in all MRT cell lines tested. Preincubation with the pancaspase inhibitor
zVAD-fmk did not completely rescue FK228-induced cell death, although it did inhibit apoptosis. Transmission electron microscopy (TEM) showed that
FK228 could stimulate MRT cells to undergo apoptosis,
necrosis or autophagy.
FK228 converted unconjugated
microtubule-associated protein light chain 3 (LC3-I) to conjugated light chain 3 (LC3-II) and induced localization of LC3 to autophagosomes.
Apoptosis inducing factor (AIF), which plays a role in
caspase-independent cell death, translocated to the nucleus in response to
FK228 treatment. Moreover,
small interfering RNA (
siRNA) targeting of AIF prevented the morphological changes associated with autophagy and redistribution of LC3 to autophagosomes. Disrupting autophagy with
chloroquine treatment enhanced FK228-induced cell death. In vivo,
FK228 caused a reduction in
tumor size and induced autophagy in
tumor tissues. Using immunoelectron microscopy, we confirmed AIF translocation into the nucleus of FK228-induced autophagic cells in vivo. Thus,
FK228 is a novel candidate for an
antitumor agent for MRT cells.