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PubMed1999

Compatibility and stability of aplidine, a novel marine-derived depsipeptide antitumor agent, in infusion devices, and its hemolytic and precipitation potential upon i.v. administration.

Aplidine is a novel marine-derived antitumor agent isolated from the Mediterranean tunicate Aplidium albicans. The compound is pharmaceutically formulated as a lyophilized product containing 500 microg active substance per dosage unit. Prior to i.v. administration it is reconstituted with a solution composed of Cremophor EL, ethanol absolute and Water for Injection (15/15/70% v/v/v) with further dilution in 0.9% w/v sodium chloride for infusion (normal saline). The aim of this study was to investigate the compatibility of aplidine infusion solutions with polyvinyl chloride (PVC)-containing and PVC-free administration sets, and to determine the stability of aplidine after reconstitution and further dilution in infusion solutions. Furthermore, in vitro biocompatibility studies to estimate the hemolytic and precipitation potential of aplidine infusion solutions upon i.v. administration were conducted. In this study we show that sorption of aplidine to PVC and to a lesser extent to PVC-free administration set materials occurs. Also, most probably due to the presence of Cremophor EL in the infusion solution, significant leaching of diethylhexyl phtalate (DEHP) from the PVC administration set occurs. After reconstitution and dilution the drug is stable for at least 24 and 48 h, respectively, in glass containers when stored at room temperature (20-25 degrees C) and ambient light conditions. We found that aplidine should be administered in infusion concentrations equal or above 28.8 microg/ml using a PVC-free administration set consisting of a glass container and PVC-free infusion tubing. After reconstitution it must be diluted further with normal saline within 24 h after preparation and subsequently administered to the patient within 48 h. Additionally, results from the biocompatibility studies show that neither hemolysis nor precipitation of aplidine is expected upon i.v. administration.

Antineoplastic Agents↗
PubMed1995

The cyclic depsipeptide backbone of the didemnins.

An X-ray crystal analysis of phi-lactone N-¿1-¿N-¿4-¿[3- hydroxy-5-methyl-1-oxo-4-(N-L-threonylamino)heptyl]- oxy¿-2,5-dimethyl-1,3-dioxohexyl¿-L-leucyl¿-L-prolyl¿- N,O-dimethyl-L-tyrosine hydrobromide hydrate (1a), C42H66N5O11+.Br-.H2O, was obtained in order to determine the backbone folding of the macrocycle and to compare the results obtained with those reported previously for the natural product didemnin B (1b). Some differences were noted in the torsion angles of the two conformers of the hydrobromide salt, denoted (1a) and (1a'). The conformation of (1a') resembled the conformation of (1b) more closely than did that of (1a). Certain regions of both crystal backbones were more flexible than those in didemnin B; however, the transannular hydrogen bonds in both (1a) and (1a') were somewhat stronger than in (1b).

Amino Acid Sequence↗
PubMed2005

Chemoresistance to depsipeptide FK228 [(E)-(1S,4S,10S,21R)-7-[(Z)-ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8,7,6]-tricos-16-ene-3,6,9,22-pentanone] is mediated by reversible MDR1 induction in human cancer cell lines.

Histone acetylation status, an epigenetic determinant of gene transcription, is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). The potent HDAC inhibitor FK228 [(E)-(1S,4S,10S,21R)-7-[(Z)-ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8,7,6]-tricos-16-ene-3,6,9,22-pentanone] is a substrate for multidrug resistance protein (MDR1) and multidrug resistance-associated protein 1 (MRP1), both of which mediate FK228 resistance. To determine the mechanisms underlying acquired FK228 resistance, we developed four FK228-resistant cell lines from HCT-15, IGROV1, MCF7, and K562 cells by stepwise increases in FK228 exposure. Parent and resistant cells were characterized using a 70-oligomer cDNA microarray, real-time reverse transcription-polymerase chain reaction (RT-PCR), Western blot, and cytotoxicity assays. At both mRNA and protein levels, MDR1, but not MRP1 or other potential resistance genes, was strongly up-regulated in all resistant cell lines. HAT or HDAC activities were unaffected in resistant cells, consistent with a lack of cross-resistance to HDAC inhibitors that are not MDR1 substrates. FK228 was found to reversibly induce MDR1 expression by HDAC inhibition and subsequent histone hyperacetylation at the MDR1 promoter, as shown by real-time RT-PCR, Western blot, and chromatin immunoprecipitation. This study reveals a significant role of histone acetylation in MDR1 transcription, which seems to mediate FK228 resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Fungicidal action of aureobasidin A, a cyclic depsipeptide antifungal antibiotic, against Saccharomyces cerevisiae.

Aureobasidin A, an antifungal antibiotic inhibiting a wide range of pathogenic fungi, is lethal for growing cells of susceptible fungi. We did cytological studies on the mechanism of its fungicidal action against Saccharomyces cerevisiae. When cultures were treated with 5.0 micrograms of aureobasidin A per ml, the numbers of viable cells started to decrease after 2 to 3 h of incubation, and most cells had lost viability after 5 to 6 h. When cell death in the treated cultures began, amino acids released by the cells could be detected, indicating disruption of the cell membrane. The proportion of cells with a single small bud or two or more buds increased as the population of viable cells decreased. Most such cells had the DNA content of cells in the G2 phase of the cell cycle, suggesting that the drug inhibited some cellular process involved in normal bud growth but did not affect DNA replication. Disruption of actin assembly was found in many cells treated for 2 to 3 h, as was chitin delocalization. The results suggest that aureobasidin A has a previously unknown mechanism of fungicidal action toward S. cerevisiae. It causes aberrant actin assembly, inhibiting the normal budding process and leading to cell death, probably through destruction of membrane integrity.

Actins↗
PubMed1994

Action of FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum no. 968, on Ha-ras transformed NIH3T3 cells.

FR901228, a novel antitumor antibiotic, reversed the transformed morphology of the Ha-ras transformants, Ras-1 cells, and inhibited their growth. The reduction of c-myc expression was observed in FR901228-treated Ras-1 cells by RNA dot-blot hybridization. This reduction of c-myc expression and morphological reversion of the transformed cells to normal were correlated with growth inhibition (G0/G1 arrest in cell cycle).

3T3 Cells↗
PubMed2001

Cryptophycins: a novel class of potent antimitotic antitumor depsipeptides.

The antitumor cryptophycins are synthetic derivatives of the desipeptide cryptophycins isolated from the cyanobacterium Nostoc sp. Cryptophycin 52 that is currently in clinical trial in solid tumors, is prepared by total synthesis of four key fragments that are coupled to form the final product. The mechanism of anticancer activity of the cryptophycins has been associated with their destabilization of microtubules and with their induction of bcl-2 phosphorylation leading to apoptosis. The cryptophycins maintain activity against ovarian and breast carcinoma cells that overexpress the multidrug resistance efflux pump P-glycoprotein. Cryptophycin 52 has demonstrated a broad range of antitumor activity against both murine and human tumors. In the human MX-1 breast carcinoma xenograft cryptophycin 55 produced greater-than- additive tumor response in combination with 5-fluorouracil. In human non-small cell lung carcinoma and human small cell carcinoma xenografts, administration of the cryptophycins along with gemcitabine, cisplatin or carboplatin resulted in antitumor activity greater than either agent alone. The cryptophycins appear to be additive with fractionated radiation therapy in the human H460 non-small cell lung carcinoma. In the human HCT116 colon carcinoma, the cryptophycins resulted in a greater than additive tumor response when administered sequentially with 5-fluorouracil or irinotecan. Treatment of animals bearing intraperitoneal human OVCAR-2 ovarian carcinoma with cryptophycin 52 resulted in survival times that were greater than those achieved with docetaxel or paclitaxel. Cryptophycin 52 is currently in early clinical testing.

Animals↗
PubMed1988

A83586C, a new depsipeptide antibiotic.

A culture identified as Streptomyces karnatakensis was found to produce a novel cyclic hexadepsipeptide antibiotic designated A83586C. The structure was elucidated by X-ray crystallography, and full 1H and 13C NMR assignments are reported. The absolute configuration was confirmed by the detection of D-threonine in the acid hydrolysate of A83586C. A83586C had potent Gram-positive activity in vitro but lacked in vivo efficacy in mice.

Animals↗
PubMed1994

FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. III. Antitumor activities on experimental tumors in mice.

The antitumor activities of FR901228, (E)-(1S,4S,10S,21R)-7-[(Z)- ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23- tetraazabicyclo[8,7,6]-tricos-16-ene-3,6,9,19,22-pentanone, isolated from Chromobacterium violaceum No. 968, were studied in animals. FR901228 (ip) prolonged the life of mice bearing such murine ascitic tumors as P388 and L1210 leukemias and B16 melanoma, and inhibited (iv) the growth of murine solid tumors (Colon 38 carcinoma, M5076 reticulum cell sarcoma and Meth A fibrosarcoma) and human solid tumors (Lu-65 and LC-6 lung carcinomas, and SC-6 stomach adenocarcinoma) implanted in normal and nude mice, respectively. Its antitumor activity was especially potent against murine Meth A fibrosarcoma and human SC-6 stomach adenocarcinoma which were refractory to mitomycin C or cisplatin. FR901228 also was more effective against mitomycin C-, cyclophosphamide-, vincristine- and 5-fluorouracil-resistant P388 leukemias than against non-resistant P388 in mice. These results suggest that FR901228 will be a new type of drug for the treatment of cancer.

Animals↗
PubMed2002

FK228 (depsipeptide) as a natural prodrug that inhibits class I histone deacetylases.

FK228 is a histone deacetylase (HDAC) inhibitor, the molecular mechanism of inhibition of which has been unknown. Here we show that reduction of an intramolecular disulfide bond of FK228 greatly enhanced its inhibitory activity and that the disulfide bond was rapidly reduced in cells by cellular reducing activity involving glutathione. Computer modeling suggests that one of the sulfhydryl groups of the reduced form of FK228 (redFK) interacts with the active-site zinc, preventing the access of the substrate. HDAC1 and HDAC2 were more strongly inhibited by redFK than HDAC4 and HDAC6. redFK was less active than FK228 in inhibiting in vivo HDAC activity, due to rapid inactivation in medium and serum. Thus, FK228 serves as a stable prodrug to inhibit class I enzymes and is activated by reduction after uptake into the cells. The glutathione-mediated activation also implicates its clinical usefulness for counteracting glutathione-mediated drug resistance in chemotherapy.

Amino Acid Sequence↗
PubMed2005

Effect of the histone deacetylase inhibitor depsipeptide on B-cell differentiation in both TEL-AML1-positive and negative childhood acute lymphoblastic leukemia.

The fusion protein TEL-AML1 in t(12;21)+ acute lymphoblastic leukemia (ALL) recruits co-repressors and histone deacetylases (HDAC), which transrepress AML1 target genes. Normal bone marrow cells were more resistant to HDAC inhibitor FK228 induced cell killing than were cells from ALL patients with or without t(12;21). FK228 induced differentiation in ALL, irrespective of the presence of t(12;21).

Antibiotics, Antineoplastic↗
PubMed2001

Effects of hydrogen-bond deletion on peptide helices: structural characterization of depsipeptides containing lactic acid.

The insertion of alpha-hydroxy acids into peptide chains provides a convenient means for investigating the effects of hydrogen bond deletion on polypeptide secondary structures. The crystal structures of three oligopeptides containing L-lactic acid (Lac) residue have been determined. Peptide 1, Boc-Val-Ala-Leu-Aib-Val-Lac-Leu-Aib-Val-Ala-Leu-OMe (Boc: tert-butyloxycarbonyl; Aib: alpha- aminoisobutyric acid; OMe: methyl ester), and peptide 2, Boc-Val-Ala-Leu-Aib-Val-Lac-Leu-Aib-Val-Leu-OMe, adopt completely helical conformations in the crystalline state with the Lac(6) residue comfortably accommodated in the center of a helix. The distance between the O atoms of Leu(3) CO group and the Lac(6) O (ester) in both the structures is 3.1-3.3 A. The NMR and CD studies of peptide 1 and its all-amide analogue 4, Boc-Val-Ala-Leu-Aib-Val-Ala-Leu-Aib-Val-Ala-Leu-OMe, provide firm evidence for a continuous helical conformation in solution in both the cases. In a 14-residue peptide 3, Boc-Val-Ala-Leu-Aib-Val-Ala-Leu-Val-Ala-Leu-Aib-Val-Lac-Leu-OMe, residues Val(1)-Leu(10) adopt a helical conformation. Aib(11) is the site of chiral reversal resulting in helix termination by formation of a Schellman motif. Residues 12-14 adopt nonhelical conformations. The loss of the hydrogen bond near the C-terminus appears to facilitate the chiral reversal at Aib(11). Published 2001 John Wiley & Sons, Inc. Biopolymers 59: 276-289, 2001

Amino Acid Sequence↗