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At least 19 recordsLinked to original sources

PubMed2004

Selective efficacy of depsipeptide in a xenograft model of Epstein-Barr virus-positive lymphoproliferative disorder.

BACKGROUND: Immune-compromised individuals are at increased risk for developing aggressive Epstein-Barr virus (EBV)-associated lymphoproliferative disorders after primary EBV infection or for reactivation of a preexisting latent EBV infection. We evaluated the effect of depsipeptide, a histone deacetylase inhibitor, on EBV-positive lymphoblastoid cell lines (LCLs) and Burkitt lymphoma cell lines in a mouse model and explored its mechanism of action in vitro. METHODS: We studied EBV-transformed LCLs, which express a latent III (Lat-III) viral gene profile, as do some EBV-positive lymphoproliferative malignancies, and Burkitt lymphoma cell lines, which express a Lat-I viral gene profile. Cell lines were used to characterize depsipeptide-induced apoptosis, which was evaluated by flow cytometry. Flow cytometry, western blot analyses, and histone deacetylase inhibitors were used to investigate components of prodeath and survival pathways in vitro. We studied depsipeptide's effects on survival with a mouse xenograft model of EBV-positive human B-cell tumors (groups of 10 mice). All statistical tests were two-sided. RESULTS: Depsipeptide (5 mg/m2 of body surface area) treatment was associated with statistically significantly improved survival of mice carrying Lat-III EBV-positive LCL tumors, compared with that of control-treated mice (day 30: for depsipeptide-treated mice, 90% survival, 95% confidence interval [CI] = 73.2% to 100%; for control-treated mice, 20% survival, 95% CI = 5.79% to 69.1%; P<.001), but it was not associated with survival of mice carrying Lat-I EBV-positive Burkitt lymphoma tumors. Depsipeptide induced apoptosis in 64% of LCLs and in 14% of EBV-positive Burkitt lymphoma cells in vitro. Depsipeptide-treated LCL cultures had two distinct cell populations--one sensitive and one resistant to depsipeptide. Depsipeptide-mediated apoptosis was associated with a 12-fold increased level of active caspase 3, but some apoptosis persisted despite z-VAD-fmk treatment to inhibit caspase activity. Depsipeptide-resistant LCLs expressed higher levels of latent membrane protein 1 (LMP1; P = .017), BCL2 (P = .032), and nuclear factor kappaB (NF-kappaB) (P<.001) than depsipeptide-sensitive LCLs; this resistance was circumvented by treatment with PS-1145, an inhibitor of NF-kappaB activation (P<.001). CONCLUSIONS: Apoptosis is induced by depsipeptide via caspase-dependent and -independent pathways in Lat-III EBV-positive LCLs and is enhanced by inhibiting NF-kappaB activity. Depsipeptide as a treatment for Lat-III EBV-associated lymphoproliferative disorders should be explored further in clinical trials.

Animals↗

PubMed2003

Enhancement of depsipeptide-mediated apoptosis of lung or esophageal cancer cells by flavopiridol: activation of the mitochondria-dependent death-signaling pathway.

OBJECTIVE: Treating cancer cells with depsipeptide, a novel antitumor agent currently in a phase II clinical trial, causes potent upregulation of p21/WAF1 expression and cell arrest at G1 and G2 checkpoints. p21/WAF1 upregulation, however, impedes the ability of depsipeptide to induce significant apoptosis. This study was designed to determine whether flavopiridol, a synthetic cyclin-dependent kinase inhibitor known to inhibit p21 expression in tumor cells, could enhance depsipeptide-mediated apoptosis in cultured lung and esophageal cancer cells. METHODS: Lung or esophageal cancer cells were exposed to depsipeptide, flavopiridol, or a combination of depsipeptide and flavopiridol. Cytotoxicity and apoptosis were quantitated by means of (4,5-dimethylthiazo-2-yl)-2,5-diphenyl tetrazolium bromide and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling-based assays, respectively. Cytosolic cytochrome c levels, caspase 9 activity, mitochondrial membrane depolarization, and dependence of apoptosis on caspase 9 in treated cells were studied to determine the role of the mitochondria in mediating apoptosis induced by this drug combination. RESULTS: Flavopiridol completely abolished depsipeptide-mediated dose-dependent upregulation of p21/WAF1 expression. Combining flavopiridol with depsipeptide resulted in a 3- to 8-fold reduction of depsipeptide inhibitory concentration of 50% values that was closely paralleled by synergistic enhancement of apoptosis (4- to 10-fold higher than levels of cell death induced by either drug alone) in all cancer cell lines. The essential role of mitochondria in mediating cell death was indicated by robust translocation of cytochrome c from the mitochondria into the cytosol, 2.5- to 5-fold activation of caspase 9, severe disruption of mitochondrial inner membrane potential, and complete inhibition of apoptosis by the selective caspase 9 inhibitor. More important, this drug combination was not toxic to primary normal epithelial cells derived from the airway or skin. CONCLUSION: The depsipeptide plus flavopiridol combination exhibits powerful and selective cytocidal activity against cancer but not normal cells. Apoptosis induced by this combination is mediated by the mitochondria-dependent death pathway.

Antineoplastic Agents↗

PubMed2006

Histone deacetylase inhibitor depsipeptide represses nicotinamide N-methyltransferase and hepatocyte nuclear factor-1beta gene expression in human papillary thyroid cancer cells.

Nicotinamide N-methyltransferase (NNMT) catalyzes N-methylation of nicotinamide and other structural analogues. NNMT gene expression is enhanced in many papillary thyroid cancer cells and activated by hepatocyte nuclear factor (HNF)-1beta. In this work, we studied the effects of depsipeptide, a histone deacetylase inhibitor, on NNMT gene expression in BHP 18-21 papillary thyroid cancer cells. Depsipeptide reduced NNMT mRNA level in a dose-dependent and time-dependent manner as determined by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR). In contrast, expression of the sodium iodide symporter (NIS), a gene with differentiated function, waas enhanced in the treated cells. NNMT protein level determined by Western blot analysis and NNMT catalytic activity was also reduced significantly in the depsipeptide-treated cells. To study the mechanism of NNMT gene repression by depsipeptide, effects of depsipeptide on NNMT promoter activity were determined by luciferase reporter gene assay. NNMT promoter activity was significantly reduced in the HNF-1beta-positive BHP 18-21 cells but not in the HNF-1beta-negative BHP 14-9 papillary cancer cells. A mutant reporter construct with mutations in a HNF-1 site in the NNMT basal promoter region did not respond to depsipeptide in both HNF-1beta protein levels, and abolished activity of DNA binding to the HNF-1 site in the NNMT promoter region. Protein synthesis inhibitor cycloheximide and proteasome inhibitor MG-132 enhanced HNF-1beta stability in the depsipeptide-treated cells. In summary, depsipeptide represses NNMT and HNF-1beta gene expression in some papillary thyroid cancer cells. the repression of NNMT by depsipeptide is at the transcription level through downregulation of transcription activator HNF-1beta.

Blotting, Western↗

PubMed2006

Increased MDR1 expression in normal and malignant peripheral blood mononuclear cells obtained from patients receiving depsipeptide (FR901228, FK228, NSC630176).

The increased expression of markers associated with a differentiated phenotype, such as P-glycoprotein (Pgp), follows treatment with histone deacetylase inhibitors. Because depsipeptide (FR901228, FK228, NSC630176) is a substrate for Pgp, up-regulation of the gene that encodes it, MDR1, would mean that depsipeptide induces its own mechanism of resistance. To examine the effect of depsipeptide on expression of ATP-binding cassette transporters associated with multidrug resistance, the kidney cancer cell lines 108, 121, 127, and 143 were treated with depsipeptide and evaluated by quantitative reverse transcription-PCR. Increased levels of MDR1 (1.3- to 6.3-fold) and ABCG2 (3.2- to 11.1-fold) but not MRP1 (0.9- to 1.3-fold) were observed. The induced Pgp transported the fluorescent substrates rhodamine 123, bisantrene, calcein-AM, BODIPY-vinblastine, and BODIPY-paclitaxel. In normal peripheral blood mononuclear cells (PBMC) and circulating tumor cells obtained from patients receiving depsipeptide, increased levels of histone H3 acetylation were found. We next examined MDR1 levels in normal and malignant PBMCs obtained from 15 patients enrolled in clinical trials with depsipeptide and detected up to a 6-fold increase in normal PBMCs and up to an 8-fold increase in circulating tumor cells after depsipeptide administration. In one patient with Sézary syndrome, increased MDR1 gene expression was accompanied by increased cell surface Pgp expression in circulating Sézary cells as determined by measurement of MRK-16 staining by flow cytometry. These studies suggest that depsipeptide induces its own mechanism of resistance and thus provide a basis for clinical trials evaluating depsipeptide in combination with a Pgp inhibitor.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Analysis of histone deacetylase inhibitor, depsipeptide (FR901228), effect on multiple myeloma.

Multiple myeloma (MM) is a neoplastic proliferation of plasma cells and remains an incurable disease because of the development of drug resistance. Histone deacytylase (HDAC) inhibitors are a new class of chemotherapeutic reagents that cause growth arrest and apoptosis of neoplastic cells. Depsipeptide, a new member of the HDAC inhibitors, was found to be safe in humans and has been shown to induce apoptosis in various cancers. In order to evaluate the effects of depsipeptide, a MM cell line, U266 [interleukin (IL)-6 dependent], was analysed for viability and apoptosis. The combined effect of depsipeptide with melphalan and changes in BCL-2 family proteins (BCL-2, BCL-XL, BAX and MCL-1) were also investigated. In addition, the RPMI 8226 cell line (IL-6 independent), and primary patient myeloma cells were also analysed for apoptosis after depsipeptide treatment. Depsipeptide induced apoptosis in both U266 and RPMI 8226 cell lines in a time- and dose-dependent fashion, and in primary patient myeloma cells. We also demonstrated that depsipeptide had an additive effect with melphalan (10 micromol/l). BCL-2, BCL-XL and MCL-1 showed decreased expression in depsipeptide-treated samples. Based on recent clinical trials demonstrating minimal clinical toxicity, our study supports the future clinical utilization of depsipeptide in the management of MM.

Antibiotics, Antineoplastic↗

PubMed2006

Cardiotoxicity of histone deacetylase inhibitor depsipeptide in patients with metastatic neuroendocrine tumors.

PURPOSE: This phase II study was undertaken to assess objective response and toxicity of histone deacetylase inhibitor depsipeptide in patients with neuroendocrine tumors. EXPERIMENTAL DESIGN: A total of 15 patients with metastatic neuroendocrine tumors received a 4-hour i.v. infusion of depsipeptide at 14 mg/m2 on days 1, 8, and 15 every 28 days. Tumor response was assessed at 8-week intervals using Response Evaluation Criteria in Solid Tumors. Most patients were chemo-naïve (n = 12) but receiving long-acting octreotide for carcinoid syndrome (n = 11). All patients had Eastern Cooperative Oncology Group performance status of 0 to 1. RESULTS: The study was terminated prematurely due to an unexpected high number of serious cardiac adverse events so the objective response rate could not be determined. A total of 77 doses of depsipeptide with a median of four doses (range, 2-13) per patient were administered. The most common adverse events included nausea (86%), anorexia (73%), vomiting (66%), and fatigue (73%). A sudden death attributed to possible fatal ventricular arrhythmia occurred within 24 hours after the fifth dose of depsipeptide. Furthermore, asymptomatic grade 2 ventricular tachycardia (n = 2) and prolonged QTc (n = 3) probably related to depsipeptide were observed. Plasma depsipeptide levels measured in a subset of patients failed to reveal differences among patients with or without cardiac adverse events. CONCLUSIONS: Depsipeptide was associated with a high number of potentially serious cardiac adverse events in patients with metastatic neuroendocrine tumor. As sudden death possibly associated with depsipeptide was observed in this trial, the risks for potentially life-threatening arrhythmia associated with this agent need to be comprehensively evaluated.

Adult↗

PubMed2004

T-cell lymphoma as a model for the use of histone deacetylase inhibitors in cancer therapy: impact of depsipeptide on molecular markers, therapeutic targets, and mechanisms of resistance.

Depsipeptide (FK228) is a novel histone deacetylase inhibitor currently in clinical trials and the first to demonstrate clinical activity in patients. Responses have been observed in patients with T-cell lymphomas, despite prior treatment with multiple chemotherapeutic agents. To better understand the effects of histone deacetylase inhibitors on T-cell lymphoma, the human T-cell lymphoma cell line HUT78 was tested for sensitivity and molecular response to depsipeptide. Treatment with depsipeptide, as well as other histone deacetylase inhibitors, caused induction of histone acetylation, induction of p21 expression, and substantial apoptosis without significant cell cycle arrest. Treatment with the caspase inhibitor z-VAD-fmk significantly inhibited depsipeptide-induced apoptosis, enabling detection of cell cycle arrest. Treatment with depsipeptide increased expression of the interleukin-2 (IL-2) receptor, and combination with the IL-2 toxin conjugate denileukin diftitox resulted in more than additive toxicity. Cells selected for resistance to depsipeptide overexpressed the multidrug resistance pump, P-glycoprotein (Pgp). However, cells selected for resistance to depsipeptide in the presence of a Pgp inhibitor had a Pgp-independent mechanism of resistance. These studies confirm the activity of depsipeptide in a T-cell lymphoma model and suggest a general sensitivity of T-cell lymphoma to histone deacetylase inhibitors, an emerging new class of anticancer agents.

Antineoplastic Agents↗

PubMed2004

Plasma and cerebrospinal fluid pharmacokinetics of depsipeptide (FR901228) in nonhuman primates.

PURPOSE: Acetylation of histones by histone acetyl transferases (HATs) leads to transcriptional activation, while histone deacetylase (HDAC) activity leads to transcriptional repression. Abnormalities of histone acetylation are associated with the malignant phenotype. Depsipeptide (FR901228) inhibits HDAC and has shown anticancer activity in preclinical models. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics of depsipeptide in a nonhuman primate model that is highly predictive of human CSF penetration. DESIGN: Depsipeptide was administered intravenously at a dose of 10 mg/m(2) over 4 h to three different animals. Serial blood samples were obtained from all animals and serial CSF samples were obtained from two animals. Plasma and CSF concentrations of depsipeptide were measured using liquid chromatography/tandem mass spectrometry. Concentration-versus-time data were modeled using model-independent and model-dependent methods. RESULTS: The peak plasma concentration (median+/-SD) was 245+/-50 n M and occurred within the first 2 h of the infusion. The terminal half-life was 205+/-315 min, the AUC extrapolated to infinity was 50+/-15 micro M.min, and the total body clearance was 350+/-65 ml/min/m(2). In the two animals that had CSF sampling performed, the CSF peak concentration was 3.6 n M in one animal and 2.3 n M in the other, and the CSF half-lives were 250 and 325 min. The CSF penetration of depsipeptide (AUC(CSF):AUC(plasma)) was 2% in each animal. Observed changes included anorexia, fatigue, elevation of creatine phosphokinase (CPK) enzyme levels (muscle fraction), and transient early leukopenia. All animals recovered without sequelae. CONCLUSIONS: Although the CSF exposure to depsipeptide after intravenous administration was only 2%, CSF concentrations approached the IC(50) of depsipeptide in vitro for some tumors. Systemic administration of this agent may be useful for the treatment of leptomeningeal tumors.

Animals↗

PubMed2005

Depsipeptide (FR901228) enhances the cytotoxic activity of TRAIL by redistributing TRAIL receptor to membrane lipid rafts.

TRAIL (TNF-related apoptosis-inducing ligand) induces apoptosis in various tumor cell types and is under investigation as a cancer therapeutic. The development of a recombinant adenovirus encoding the full-length human TRAIL gene (Ad5-TRAIL) replaces the need for large quantities of soluble TRAIL protein in tumor suppressive therapies. However, the full potential of Ad5-TRAIL has not yet been maximized. Recent investigation of a histone deacetylase inhibitor, depsipeptide (FR901228), has demonstrated that it increases cellular susceptibility to adenovirus infection and augments adenoviral transgene expression. Thus, studies were initiated to evaluate the ability of depsipeptide to enhance the cytotoxic activity of Ad5-TRAIL against human prostate tumor cells. In vitro, depsipeptide increased expression of coxsackie-adenovirus receptor, leading to increased adenoviral infection and transgene expression. Additionally, tumor cell killing by Ad5-TRAIL was higher following depsipeptide pretreatment. More surprisingly, depsipeptide also increased prostate tumor cell sensitivity to TRAIL-induced apoptosis. Investigation into the mechanism responsible for increased TRAIL responsiveness revealed increased levels of TRAIL-R1 and -R2 in membrane lipid rafts following depsipeptide treatment. These results indicate that depsipeptide is a potent agent for enhancing the activity of Ad5-TRAIL by multiple mechanisms, allowing for a more efficient use of Ad5-TRAIL as an antitumor therapy.

Adenoviridae↗

PubMed2006

Evaluation of the antitumor efficacy, pharmacokinetics, and pharmacodynamics of the histone deacetylase inhibitor depsipeptide in childhood cancer models in vivo.

PURPOSE: Histone acetyltransferases and histone deacetylases (HDAC) control the acetylation state of histones and other proteins regulating transcription and protein function. Several structurally diverse HDAC inhibitors have been developed as cancer therapeutic agents and in vitro have been shown to cause differentiation, cell cycle arrest, or apoptosis. Here, we have evaluated depsipeptide, a natural tetrapeptide HDAC inhibitor, against a panel of pediatric solid tumor models in vivo and evaluated pharmacokinetic and pharmacodynamic variables with tumor sensitivity. EXPERIMENTAL DESIGN: Depsipeptide was administered at the maximum tolerated dose (4.4 mg/kg administered every 7 days x 3 i.v. repeated q21d for a total of two cycles) to scid mice bearing 39 independently derived childhood tumors (9 brain tumors, 11 kidney cancers, 9 rhabdomyosarcomas, 3 neuroblastomas, and 7 osteosarcomas). Pharmacokinetic variables were determined, as were changes in histone and p53 acetylation, induction of p53 and p53 genotype, and alterations in Akt phosphorylation. RESULTS: Of 39 tumors evaluated, three showed objective tumor regressions [two brain tumors (primitive neuroectodermal tumor and atypical teratoid malignant rhabdoid tumor) and one Wilms' tumor]. Depsipeptide inhibited growth of many tumor lines but achieved stable disease (<25% increase in volume during treatment cycle 1) in only two tumor models (anaplastic astrocytoma, two rhabdomyosarcomas, and a Wilms' tumor). Pharmacokinetic analysis showed that the population estimated AUC(0-24) was 1,123 ng h/mL, similar to the exposure following 13 mg/m2 in ongoing phase I trials. Pharmacodynamic changes in histone acetylation (H2A, H2B, H3, and H4) in three depsipeptide-sensitive and three intrinsically resistant tumors followed a similar pattern; maximal increases in histone acetylation occurred at 8 hours and were elevated for up to 96 hours. In two sensitive tumor lines, IRS56 and BT27 (both wild-type p53) p53 increased in treated tumors being maximal at 8 hours and associated with induction of p21(cip1), whereas p53 was stable in tumors with mutant p53. Sensitivity to depsipeptide did not correlate with p53 genotype, p53 acetylation, cleaved poly(ADP-ribose) polymerase, or phosphorylation of Akt (Ser473). CONCLUSIONS: Our results show that depsipeptide inhibits its target in vivo causing increased histone acetylation; however, this does not correlate with drug sensitivity. The relatively low objective response rate [3 of 39 (8%) tumor lines showing greater than or equal to partial response and 4 (10%) stable disease] administered at dose levels that give clinically relevant drug exposures suggests that as a single agent depsipeptide may have limited clinical utility against pediatric solid tumors in a first-line setting.

Acetylation↗

PubMed1999

Depsipeptide (FR901228): a novel therapeutic agent with selective, in vitro activity against human B-cell chronic lymphocytic leukemia cells.

Therapy of B-cell chronic lymphocytic leukemia (CLL) has been limited by both the nonselectivity of therapeutic agents toward normal residual immune cells and inherent drug resistance. Identification of agents that spare normal immune effector cells, thus facilitating addition of immune-based therapies, and that modulate factors associated with drug resistance in CLL might represent a major therapeutic advance. Depsipeptide (FR901228) is a novel agent entering clinical trials that has selective in vitro activity against resistant leukemia cell lines. To assess its in vitro activity in CLL, we exposed peripheral mononuclear cells from CLL patients (n = 10) to varying concentrations of this agent. Viability of the CLL cells was reduced by 50% (LC(50)) at 4 hours, 24 hours, and 4 days at depsipeptide concentrations of 0.038, 0.024, and 0.015 micromol/L, respectively. Depsipeptide had marked selective cytotoxicity when compared with normal blood mononuclear cells, in which the LC(50) was 3.44 micromol/L at 4 hours (P =.03), 0.965 micromol/L at 24 hours (P =.01), and 0.0318 micromol/L at 96 hours (P =.04). Inhibition of bone marrow progenitor cell growth was also minimal after incubation with 0.015 micromol/L (19% inhibition of colony forming unit-granulocyte-macrophage [CFU-GM]; 17% inhibition burst forming unit-erythroid [BFU-E]) and 3.44 micromol/L (24% inhibition of CFU-GM; 57% inhibition BFU-E) of depsipeptide for 4 hours, followed by a 14-day incubation period. Expression of apoptotic proteins after depsipeptide exposure (0.015 micromol/L) included no change in bcl-2, elevation of bax, and decreased expression of p27. These data demonstrate that depsipeptide has significant selective in vitro activity against human CLL cells concurrent with favorable alterations of the bcl-2:bax protein ratio and decrease in p27 expression. Such findings strongly support the early introduction of depsipeptide into clinical trials for patients with CLL.

Anti-Bacterial Agents↗

PubMed2002

Recent developments in depsipeptide research.

This review focuses on the major developments in depsipeptide research since 1995. Depsipeptides are bio-oligomers composed of hydroxy and amino acids linked by amide and ester bonds. Many depsipeptides show very promising biological activities, including anticancer, antibacterial, antiviral, antifungal, anti-inflammatory, and anti-clotting or anti-antherogenic properties. In this report depsipeptides exhibiting these properties are discussed. Their isolation, structural determination, and notable structural features are discussed, but their biological properties and therapeutic potentials are emphasized. Depsipeptides have shown the greatest therapeutic potential as anticancer agents. Four depsipeptides have entered clinical trials for cancer treatment. Among the antiviral compounds discovered, the callipeltins and the quinoxapeptins are particularly promising due to their inhibitory activities against HIV. These compounds have the potential to be developed as anti-AIDS drugs or to serve as lead compounds for the discovery of structurally related anti-AIDS compounds. Antifungal compounds, such as the jaspamides, may lead to therapies against many of the opportunistic infections that accompany AIDS. Anti-inflammatory compounds such as SCH217048 act as neurokinin antagonists and may lead to anti-inflammatory treatments. Some depsipeptides such as micropeptins and A90720A have been found to be effective plasmin inhibitors, which have implications as treatments for cardiovascular diseases. Compounds such as SCH58149 help control the levels of HDL and LDL.

Anti-Inflammatory Agents↗

PubMed2005

Involvement of the tumor necrosis factor (TNF)/TNF receptor system in leukemic cell apoptosis induced by histone deacetylase inhibitor depsipeptide (FK228).

Inhibition of histone deacetylase (HDAC) is a novel strategy for the treatment of leukemias via restoration of aberrantly silenced genes. In this study, we conducted a detailed analysis of anti-leukemic effects of an HDAC inhibitor (HDI), depsipeptide (FK228), using myeloid leukemia cell lines HL-60 and K562. DNA chip analysis revealed upregulation of TNF-alpha mRNA and a number of molecules involved in TNF-signaling such as TRAF-6, caspases-10, and -7 in depsipeptide-treated HL-60 cells, which prompted us to examine the involvement of the TNF/TNF receptor system in the anti-leukemic effects of the drug. Upregulation of TNF-alpha was induced by depsipeptide in HL-60 and K562 cells, which expressed type I TNF receptors (TNF-RI). Depsipeptide activated caspases-8 and -10, which in turn cleave caspases-3 and -7, leading to apoptotic cell death in both cell lines. Anti-TNF-alpha neutralizing antibody and short interfering RNA (siRNA) against TNF-RI alleviated the activation of the caspase cascade and the induction of apoptosis, indicating the presence of an autocrine loop. Finally, we demonstrated that the enhanced production of TNF-alpha by depsipeptide was due to transcriptional activation of the TNF-alpha gene through hyperacetylation of histones H3 and H4 in its promoter region (-208 to +35). These results suggest that autocrine production of TNF-alpha plays a role in the cytotoxicity of depsipeptide against a subset of leukemias.

Acetylation↗

PubMed2005

Depsipeptide-resistant KU812 cells show reversible P-glycoprotein expression, hyper-acetylated histones, and modulated gene expression profile.

Depsipeptide (FK228), a histone deacetylase inhibitor, is a promising new anticancer agent. The mechanism of resistance to this agent was studied using KU812 cells. Depsipeptide-resistant KU812 cells expressed P-glycoprotein (P-gp) and their resistance was abolished by co-treatment with verapamil. P-gp expression returned to the parental cell level when resistant cells were cultured in depsipeptide-free medium, while resistant cells cultured in the medium containing 16 nM depsipeptide still showed hyper-acetylation of histones. Moreover, resistant cells showed erythroid differentiation. Microarray analysis revealed that 28 genes showed increased expression and three genes showed decreased expression in resistant cells compared with parental cells. These 31 genes had various functions relating to signal transduction, cell cycle, apoptosis, and control of cell morphology and differentiation. Among the 28 genes that were upregulated, 15 genes also showed an increased expression in parental cells treated with 4 nM depsipeptide for 48 h, while the other 13 genes including P-gp were different. Among the three genes with decreased expression, HEP27 was most dramatically downregulated. These findings suggest that continuous exposure to depsipeptide reversibly induces P-gp, which contributes to the onset of resistance, but the altered gene expression profile of resistant cells may also play a role.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

Systemic co-administration of depsipeptide selectively targets transfection enhancement to specific tissues and cell types.

Depsipeptide, a histone deacetylase (HDAC) inhibitor, kills tumor cells much more effectively than normal cells, and can produce significant antitumor activity in human cancer patients. Depsipeptide also increases the expression of lipoplex-delivered genes in cultured tumor cells, as well as following direct intra-tumoral injection. We now show that co-intravenous (i.v.) injection of depsipeptide with polyethylenimine (PEI):DNA complexes significantly increases the expression of PEI-delivered genes in normal, as well as in tumor-bearing mice. At the tissue level, depsipeptide-mediated enhancement of gene expression was selectively targeted to the lung, liver and spleen. At the cellular level, depsipeptide significantly increased the expression of the i.v., PEI co-delivered wild-type human p53 gene in metastatic breast cancer cells, but not in adjacent normal cells. Thus, the ability of depsipeptide to enhance the expression of systemically delivered genes is selectively targeted at both the tissue and cellular levels, without requiring the use of ligand- or promoter-based approaches. Analyzing HDAC-based targeting of gene expression may identify host genes that control the expression of systemically delivered genes.

Animals↗

PubMed2006

Acetylation of p53 at lysine 373/382 by the histone deacetylase inhibitor depsipeptide induces expression of p21(Waf1/Cip1).

Generally, histone deacetylase (HDAC) inhibitor-induced p21(Waf1/Cip1) expression is thought to be p53 independent. Here we found that an inhibitor of HDAC, depsipeptide (FR901228), but not trichostatin A (TSA), induces p21(Waf1/Cip1) expression through both p53 and Sp1/Sp3 pathways in A549 cells (which retain wild-type p53). This is demonstrated by measuring relative luciferase activities of p21 promoter constructs with p53 or Sp1 binding site mutagenesis and was further confirmed by transfection of wild-type p53 into H1299 cells (p53 null). That p53 was acetylated after depsipeptide treatment was tested by sequential immunoprecipitation/Western immunoblot analysis with anti-acetylated lysines and anti-p53 antibodies. The acetylated p53 has a longer half-life due to a significant decrease in p53 ubiquitination. Further study using site-specific antiacetyllysine antibodies and transfection of mutated p53 vectors (K319/K320/K321R mutated and K373R/K382R mutations) into H1299 cells revealed that depsipeptide specifically induces p53 acetylation at K373/K382, but not at K320. As assayed by coimmunoprecipitation, the K373/K382 acetylation is accompanied by a recruitment of p300, but neither CREB-binding protein (CBP) nor p300/CBP-associated factor (PCAF), to the p53 C terminus. Furthermore, activity associated with the binding of the acetylated p53 at K373/K382 to the p21 promoter as well as p21(Waf1/Cip1) expression is significantly increased after depsipeptide treatment, as tested by chromatin immunoprecipitations and Western blotting, respectively. In addition, p53 acetylation at K373/K382 is confirmed to be required for recruitment of p300 to the p21 promoter, and the depsipeptide-induced p53 acetylation at K373/K382 is unlikely to be dependent on p53 phosphorylation at Ser15, Ser20, and Ser392 sites. Our data suggest that p53 acetylation at K373/K382 plays an important role in depsipeptide-induced p21(Waf1/Cip1) expression.

Acetylation↗

PubMed2004

A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia.

Preclinical studies with the histone deacetylase (HDAC) inhibitor depsipeptide (FK228) in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) have demonstrated that it effectively induces apoptosis at concentrations at which HDAC inhibition occurs. We initiated a minimum effective pharmacologic dose study of depsipeptide, targeting an in vivo dose at which acetylation of histone proteins H3 and H4 increased by 100% or more in vitro. Ten patients with CLL and 10 patients with AML were treated with 13 mg/m(2) depsipeptide intravenously days 1, 8, and 15 of therapy. Neither life-threatening toxicities nor cardiac toxicities were noted, although the majority of patients experienced progressive fatigue, nausea, and other constitutional symptoms that prevented repeated dosing. Several patients had evidence of antitumor activity following treatment, but no partial or complete responses were noted by National Cancer Institute criteria. HDAC inhibition and histone acetylation increases of at least 100% were noted, as well as increases in p21 promoter H4 acetylation, p21 protein, and 1D10 antigen expression. We conclude that depsipeptide effectively inhibits HDAC in vivo in patients with CLL and AML, but its use in the current schedule of administration is limited by progressive constitutional symptoms. Future studies with depsipeptide should examine alternative administration schedules.

Aged↗

PubMed2006

Phase I study of depsipeptide in pediatric patients with refractory solid tumors: a Children's Oncology Group report.

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetic profile, and pharmacodynamics of the histone deacetylase inhibitor, depsipeptide, in children with refractory or recurrent solid tumors. PATIENTS AND METHODS: Depsipeptide was administered as a 4-hour infusion weekly for 3 consecutive weeks every 28 days at dose levels of 10 mg/m2, 13 mg/m2, 17 mg/m2, and 22 mg/m2. Pharmacokinetics and histone acetylation studies were performed in the first course. The levels of H3 histone and acetyl-H3 histone were evaluated in peripheral blood mononuclear cells (PBMC) using immunofluorescence techniques. RESULTS: There were 24 patients, and 18 who were assessable were enrolled. DLTs included reversible, asymptomatic T-wave inversions, without any associated changes in troponin levels or evidence of ventricular dysfunction, in the inferior leads in two patients at 22 mg/m2 and in the lateral leads in one patient at 13 mg/m2 (n = 1), and transient asymptomatic sick sinus syndrome and hypocalcemia in one patient at 17 mg/m2. At the MTD (17 mg/m2), the median depsipeptide clearance was 6.8 L/h/m(2) with an area under the plasma depsipeptide concentration-time curve from 0 to infinity of 2,414 ng/mL/h, similar to adults. Accumulation of acetylated H3 histones was seen in all patients in a dose independent manner, with maximal accumulation at a median of 4 hours, (range, 0 hours to 20 hours) after the end of the infusion. No objective tumor responses were observed. CONCLUSION: Depsipeptide is well tolerated in children with recurrent or refractory solid tumors when administered weekly for 3 consecutive weeks every 28 days and inhibits histone deacetylase activity in PBMC in a dose-independent manner. The recommended phase II dose in children with solid tumors is 17 mg/m2.

Acetylation↗