Romidepsin (FK228), a potent histone deacetylase inhibitor, induces apoptosis through the generation of hydrogen peroxide

Abstract

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 (Dwm) 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

Oxidative Stress and Lipid Peroxidation Products in Cancer Progression and Therapy

“…HDAC inhibitors lead to a wide spectrum of biological effects, including induction of apoptosis inhibition of angiogenesis, induction of cellular senescence, and induction of oxidative stress caused by mitochondrial injury. In particular, for romidepsin, it has been reported that its apoptotic action is linked to the generation of hydrogen peroxide and is prevented by N-acetyl-cysteine, thus suggesting that reactive oxygen species participate in apoptosis [133]. …”

Pirarubicin, an Anthracycline Anticancer Agent, Induces Apoptosis Through Generation of Hydrogen Peroxide

“…5×10 4 cells were seeded into each well of 96-well culture plates. After the treatment with THP for 6 or 24 h, cytotoxicity was analyzed according to the manufacturer's instructions (19).…”

Embryonic Life of Hdac Inhibitors: – In Diabetic Nephropathy

“…[24,25] HDACIs also have effects on non-histone proteins which include proteins involved in the regulation of gene expression, pathways of extrinsic and intrinsic apoptosis, cell-cycle progression, redox pathways, mitotic division, DNA repair, cell migration and angiogenesis. [2,[33][34][35][36][37][38][39] In general, amplified levels of histone acetylation lead to de-condensation of chromatin allowing DNA accessible to transcription factors, and are thus related with increased transcriptional activity, whereas decreased acetylation levels are associated with transcriptional repression. [23] A recent study, however, verified that structurally different HDAC inhibitors significantly activated or repressed more than 40% of genes on the array in cultured acute T-cell leukemia cell line.…”