Disease relevance of Depsipeptide

• Modulation of p53, ErbB1, ErbB2, and Raf-1 expression in lung cancer cells by depsipeptide FR901228 [1].
• 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 [2].
• 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 [2].
• A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia [3].
• Depsipeptide is in clinical trials for chronic lymphocytic leukemia (CLL) on the basis of earlier observations demonstrating selective in vitro activity in CLL [4].

High impact information on Depsipeptide

• SAHA and depsipeptide coordinately regulated the expression of several genes within distinct apoptosis and cell cycle pathways [5].
• APAF-1, a gene central to the intrinsic apoptotic pathway, was induced by SAHA and depsipeptide and shown to be important, but not essential, for HDACi-induced cell death [5].
• The basis for vancomycin resistance is the manufacture of the depsipeptide D-Ala-D-lactate, which is incorporated into the peptidoglycan cell wall in place of the vancomycin target D-Ala-D-Ala [6].
• Crystal and molecular structure of didemnin B, an antiviral and cytotoxic depsipeptide [7].
• beta-Lactamases from all three classes, A, B, and C, catalyze the hydrolysis of specific acyclic depsipeptide (PhCH2CONHCR1R2CO2CHR3CO2H) analogs of acyl-D-alanyl-D-alanine peptides [8].

Chemical compound and disease context of Depsipeptide

• Quantitative reverse transcription-PCR analysis revealed robust, coincident induction of BORIS and NY-ESO-1 expression in lung cancer cells, but not normal human bronchial epithelial cells following 5-aza-2'-deoxycytidine (5-azadC), Depsipeptide FK228 (DP), or sequential 5-azadC/DP exposure under clinically relevant conditions [9].
• In this work, we show that p21(WAF1) induction by HDAC inhibitors (depsipeptide and trichostatin A) is defective in Ataxia telangiectasia (AT) cells but normal in matched wild-type (WT) cells (human diploid fibroblasts) [10].
• Furthermore, NK cells expanded from patients with metastatic renal cell carcinoma were significantly more cytotoxic against autologous tumor cells when pretreated with either bortezomib or depsipeptide compared with untreated tumors [11].
• Overproduction of the L. mesenteroides D-Ala-D-Ala ligase (LmDdl) 2 in E. coli and its purification to approximately 90% homogeneity allow demonstration that the LmDdl2 does have both depsipeptide and dipeptide ligase activity [12].
• Recently, we reported that mutation of an active site tyrosine (Tyr), Tyr216, to phenylalanine (Phe) in the E. coli DdlB leads to gain of D-Ala-D-Lac depsipeptide ligase activity in that enzyme [12].

Biological context of Depsipeptide

• Active site peptides were generated by chemical or enzymatic cleavage of these carboxypeptidases after covalently labeling with [14C]penicillin G or after trapping an acyl-enzyme intermediate derived from the depsipeptide substrate [13].
• Treatment with the caspase inhibitor z-VAD-fmk significantly inhibited depsipeptide-induced apoptosis, enabling detection of cell cycle arrest [2].
• Our data suggest that p53 acetylation at K373/K382 plays an important role in depsipeptide-induced p21(Waf1/Cip1) expression [14].
• Up-regulation of MDR1 and induction of doxorubicin resistance by histone deacetylase inhibitor depsipeptide (FK228) and ATRA in acute promyelocytic leukemia cells [15].
• 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 [14].

Anatomical context of Depsipeptide

• Valinomycin is a depsipeptide antibiotic which selectively translocates potassium across biologic membranes [16].
• Treatment of cells with the histone deacetylase inhibitor FR901228 (depsipeptide) increased CAR and alpha(v) integrin RNA levels in six cancer cell lines [17].
• Bortezomib and depsipeptide sensitize tumors to tumor necrosis factor-related apoptosis-inducing ligand: a novel method to potentiate natural killer cell tumor cytotoxicity [11].
• NK cells isolated from healthy donors and patients with cancer were expanded in vitro and then tested for cytotoxicity against tumor cell lines before and after exposure to bortezomib or depsipeptide [11].
• Whereas all three drugs induce the activation of the proapoptotic Bcl-2 protein Bid upstream of mitochondrial membrane disruption, Bid cleavage in response to depsipeptide was significantly attenuated by zVAD-fmk [18].

Associations of Depsipeptide with other chemical compounds

• The combination of ATRA and the novel histone deacetylase inhibitor (HDACI) depsipeptide (FK228) induced P-gp expression and prevented growth inhibition and apoptosis in NB4 APL cells subsequently exposed to doxorubicin (DOX) [15].
• Depsipeptide-induced apoptosis is caspase dependent, selectively involving the tumor necrosis factor (TNF) receptor (extrinsic pathway) initiating caspase 8 and effector caspase 3 [4].
• Acetylation of p53 at lysine 373/382 by the histone deacetylase inhibitor depsipeptide induces expression of p21(Waf1/Cip1) [14].
• In this study, we show that a depsipeptide, FR901228, inhibited osteoclast differentiation by not only suppressing RANKL-induced nuclear translocation of NFATc1 but also increasing the mRNA level of IFN-beta, an inhibitor of osteoclastogenesis [19].
• A highly specific D-hydroxyisovalerate (D-HIV) dehydrogenase, which is a key enzyme in depsipeptide synthesis, was purified to near homogeneity from the enniatin-producing fungus Fusarium sambucinum [20].

Gene context of Depsipeptide

• 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 [21].
• Moreover, long-term treatment with a low dose of depsipeptide resulted in the induction of differentiation into hypertrophic phenotype, as shown by the increment of the alpha1 chain of type X collagen (COL10A1) expression in chondrosarcoma cells [22].
• These results suggest that autocrine production of TNF-alpha plays a role in the cytotoxicity of depsipeptide against a subset of leukemias [23].
• Notably, the activity of depsipeptide was enhanced by 5-aza-2'-deoxycytidine, a DNA methyltransferase inhibitor (DNMT) [24].
• ABCG2 did not confer appreciable resistance to etoposide, taxol or the histone deacetylase inhibitor depsipeptide [25].

Analytical, diagnostic and therapeutic context of Depsipeptide

• Such findings strongly support the early introduction of depsipeptide into clinical trials for patients with CLL [26].
• 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 [14].
• That p53 was acetylated after depsipeptide treatment was tested by sequential immunoprecipitation/Western immunoblot analysis with anti-acetylated lysines and anti-p53 antibodies [14].
• Here we report that inhibitors of histone deacetylase (HDAC), depsipeptide and trichostatin A, induce apoptotic cell death in human lung cancer cells as demonstrated by DNA flow cytometry and Western immunoblot to detect cleavage of poly(ADP-ribose) polymerase [27].
• Using semi-quantitative RT-PCR, we observed that 5-aza-2'-deoxycytidine in combination with depsipeptide produced a greater reactivation of both maspin and gelsolin as compared to each agent alone [28].

References