Romidepsin (FK228), a potent histone deacetylase inhibitor, induces apoptosis through the generation of hydrogen peroxide.
Romidepsin (FK228) is a potent histone deacetylase (HDAC) inhibitor, which has a potent anticancer activity, but its molecular mechanism is unknown. We investigated the mechanism of FK228-induced apoptosis in the human leukemia cell line HL-60 and its hydrogen peroxide (H(2)O(2))-resistant sub-clone, HP100, and the human colon cancer cell line Caco-2. Cytotoxicity and DNA ladder formation induced by FK228 could be detected in HL-60 cells after a 24-h incubation, whereas they could not be detected in HP100 cells. Trichostatin A (TSA), an HDAC inhibitor, induced DNA ladder formation in both HL-60 and HP100 cells. In contrast, FK228 inhibited HDAC activity in both HL-60 and HP100 cells to a similar extent. These findings suggest that FK228-induced apoptosis involves H(2)O(2)-mediated pathways and that TSA-induced apoptosis does not. Flow cytometry revealed H(2)O(2) formation and a change in mitochondrial membrane potential (Δψm) in FK228-treated cells. FK228 also induced apoptosis in Caco-2 cells, which was prevented by N-acetyl-cysteine, suggesting that reactive oxygen species participate in apoptosis in various types of tumor cells. Interestingly, in a cell-free system, FK228 generated superoxide (O(2)(-)) in the presence of glutathione, suggesting that H(2)O(2) is derived from dismutation of O(2)(-) produced through redox-cycle of FK228. Therefore, in addition to HDAC inhibition, H(2)O(2) generated from FK228 may participate in its apoptotic effect.
Mizutani
Hideki
H
College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan.
Hiraku
Yusuke
Y
Tada-Oikawa
Saeko
S
Murata
Mariko
M
Ikemura
Kenji
K
Iwamoto
Takuya
T
Kagawa
Yoshiyuki
Y
Okuda
Masahiro
M
Kawanishi
Shosuke
S
D000111:Acetylcysteine / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology
D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D006861:Hydrogen Peroxide; C087123:romidepsin; D005978:Glutathione; D000111:Acetylcysteine