Apicidin, a Histone Deacetylase Inhibitor, Induces Apoptosis and Fas/Fas Ligand Expression in Human Acute Promyelocytic Leukemia Cells

Abstract

We previously reported that apicidin arrested human cancer cell growth through selective induction of p21 WAF1/Cip1 . In this study, the apoptotic potential of apicidin and its mechanism in HL60 cells was investigated. Treatment of HL60 cells with apicidin caused a decrease in viable cell number in a dose-dependent manner and an increase in DNA fragmentation, nuclear morphological change, and apoptotic body formation, concomitant with progressive accumulation of hyperacetylated histone H4. In addition, apicidin converted the procaspase-3 form to catalytically active effector protease, resulting in subsequent cleavages of poly-(ADP-ribose) polymerase and p21 WAF1/Cip1 . Incubation of HL60 cells with z-DEVD-fmk, a caspase-3 inhibitor, almost completely abrogated apicidin-induced activation of caspase-3, DNA fragmentation, and cleavages of poly-(ADP-ribose) polymerase and p21 WAF1/Cip1 . Moreover, these effects were preceded by an increase in translocation of Bax into the mitochondria, resulting in the release of cytochrome c and cleavage of procaspase-9. The addition of cycloheximide greatly inhibited activation of caspase-3 by apicidin by interfering with cleavage of procaspase-3 and DNA fragmentation, suggesting that apicidin-induced apoptosis was dependent on de novo protein synthesis. Consistent with these results, apicidin transiently increased the expressions of both Fas and Fas ligand. Preincubation with NOK-1 monoclonal antibody, which prevents the Fas-Fas ligand interaction and is inhibitory to Fas signaling, interfered with apicidin-induced translocation of Bax, cytochrome c release, cleavage of procaspase-3, and DNA fragmentation. Taken together, the results suggest that apicidin might induce apoptosis through selective induction of Fas/Fas ligand, resulting in the release of cytochrome c from the mitochondria to the cytosol and subsequent activation of caspase-9 and caspase-3.

Histone deacetylase inhibitors induce apoptosis in both Type I and Type II endometrial cancer cells

“…A cowpox virus protein that inhibits caspase-8 and -10 was used to show that apoptosis in response to oxamflatin was mediated by the intrinsic pathway in a T-cell leukemia cell line. In contrast, other HDAC inhibitors such as apicidin have been shown to activate the death receptor pathway in leukemia cell lines [28]. Others have shown that administration of tumor necrosis factor-related apoptosisinducing ligand (TRAIL), known to activate the death receptor pathway, potentiates the apoptotic response in combination with HDAC inhibitors [29].…”

Sensitization of osteosarcoma cells to death receptor-mediated apoptosis by HDAC inhibitors through downregulation of cellular FLIP

“…Previous reports have shown HDAC inhibitor-induced upregulation of Fas, [18][19][20] FasL, 23 and Bax 31 and downregulation of Bcl-X L . 29,32 On the contrary, we did not observe changes in Fas and Bcl-X L expression following treatment of OST, U-2 OS, and HeLa cells with FR901228 (Figure 3b).…”

“…6 In HDAC inhibitor-induced activation of death receptor-mediated apoptosis, upregulation of Fas and FasL occurs in cells derived from neuroblastoma, 18 promyelocytic leukemia, 19 and uveal melanoma. 20 In addition, downregulation of FLIP-L protein was reportedly induced by treatment of chronic lymphocytic leukemia cells with the HDAC inhibitors FR901228 and MS-275.…”

Valproic acid inhibits histone deacetylase activity and suppresses excitotoxicity-induced GAPDH nuclear accumulation and apoptotic death in neurons

“…6 Moreover, HDAC inhibitors were found to induce apoptosis characterized by typical morphological changes. 7,8 Conversely, HDAC inhibitors were reported to be neuroprotective via enhancing the acetylation of SP1, a cytoprotective transcription factor, and that this process is necessary for the induction of antioxidant proteins. 9 Further, an HDAC inhibitor, phenylbutyrate, was found to prolong markedly life span in Drosophila, presumably through modulation of gene expression.…”