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Journal of Biochemistry Jan 2016We have investigated a number of complexes of 7-aminoactinomycin D (7AAMD), with its potential carriers: caffeine, folic acid (FA), purine bases-guanine and adenine,...
We have investigated a number of complexes of 7-aminoactinomycin D (7AAMD), with its potential carriers: caffeine, folic acid (FA), purine bases-guanine and adenine, pyrimidine base-thymine and with fragmented DNA to determine more stable and suitable complex. The process of binding of the fluorescent antibiotic with clusters of caffeine, guanine, adenine, thymine and with fragmented DNA was accompanied by a considerable long-wavelength shift in excitation spectrum. The energy of interaction between phenoxazine hetero-cycle of 7AAMD and chromophores of the carriers studied has been found. In the case of 7AAMD with guanine, adenine, thymine and caffeine, the energy is about of 7 kcal/mol, which is a little lower than in the case with DNA (7.7 kcal/mol). On the basis of emission spectra, in all examined compounds, with the exception DNA, the 7AAMD molecule emits photons from water phase, not from a cluster, since photo-excitation leads to desorption of the antibiotic from a cluster surface. We observed also the mutual fluorescence quenching of 7AAMD and FA in their complex. It may well be that this complex forms due to interaction of peptide-lactone rings of 7AAMD with system of FA. In the case of DNA, the complex with 7AAMD has very high stability that is determined not only by interaction between phenoxazine of 7AAMD and the DNA bases, but it is largely owing to the interaction between two peptide-lactone rings of 7AAMD and the DNA deoxyribose-phosphate chains.
Topics: Adenine; Antibiotics, Antineoplastic; Caffeine; DNA; Dactinomycin; Drug Carriers; Fluorescent Dyes; Folic Acid; Guanine; Nucleotides; Thymine
PubMed: 26254482
DOI: 10.1093/jb/mvv075 -
Apoptosis : An International Journal on... Jun 2022Actinomycin D (ActD) was the first anticancer antibiotic approved for the management of human cancers. However, the notorious toxicity profile limits its widespread...
Actinomycin D (ActD) was the first anticancer antibiotic approved for the management of human cancers. However, the notorious toxicity profile limits its widespread application in cancers, including cancers of the aerodigestive tract. Recent studies show that combining low-dose ActD with existing chemotherapies could potentially protect normal cells from the toxicity of chemotherapy drugs through p53 activation (cyclotherapy). An understanding of ActD's effect on p53 signaling is critical for the meaningful application of ActD in cyclotherapy-based combinations. This study evaluated the anti-tumor efficacy and mechanism of action of ActD in aerodigestive tract cancers. We found that ActD strongly inhibited the growth of a panel of aerodigestive tract cancer cell lines and induced efficient apoptosis, although the sensitivity varies among cell lines. The IC values of ActD spanned between 0.021 and 2.96 nM. Mechanistic studies revealed that ActD increased the expression of total and phosphorylated p53 (ser15) in a time- and dose-dependent manner. Moreover, ActD-induced apoptosis is dependent on p53 in cells expressing wild-type p53 and that ActD induced context-dependent differential expression of downstream targets p21 and PUMA without significant effects on p27. In the final analysis, this study revealed that p53-p21 is the predominant pathway activated by low-dose ActD, supporting further development of ActD in cyclotherapy.
Topics: Antibiotics, Antineoplastic; Apoptosis; Dactinomycin; Humans; Neoplasms; Tumor Suppressor Protein p53
PubMed: 35267106
DOI: 10.1007/s10495-022-01720-5 -
Marine Drugs Apr 2019Bioactive secondary metabolites from are important sources of lead compounds in current drug development. SCSIO ZS0073, a mangrove-derived actinomycete, produces...
Bioactive secondary metabolites from are important sources of lead compounds in current drug development. SCSIO ZS0073, a mangrove-derived actinomycete, produces actinomycin D, a clinically used therapeutic for Wilm's tumor of the kidney, trophoblastic tumors and rhabdomyosarcoma. In this work, we identified the actinomycin biosynthetic gene cluster (BGC) by detailed analyses of the SCSIO ZS0073 genome. This organism produces actinomycin D with a titer of ~69.8 μg mL along with traces of actinomycin X. The cluster localized to a 39.8 kb length region consisting of 25 open reading frames (ORFs), including a set of four genes that drive the construction of the 4-methyl-3-hydroxy-anthranilic acid (4-MHA) precursor and three non-ribosomal peptide synthetases (NRPSs) that generate the 4-MHA pentapeptide semi-lactone, which, upon dimerization, affords final actinomycin D. Furthermore, the cluster contains four positive regulatory genes , which were identified by in vivo gene inactivation studies. Our data provide insights into the genetic characteristics of this new mangrove-derived actinomycin D bioproducer, enabling future metabolic engineering campaigns to improve both titers and the structural diversities possible for actinomycin D and related analogues.
Topics: Biosynthetic Pathways; Dactinomycin; Multigene Family; Peptide Synthases; Streptomyces; ortho-Aminobenzoates
PubMed: 31018504
DOI: 10.3390/md17040240 -
Canadian Medical Association Journal Jul 1976In an unselected series of 49 children with Wilms' tumour treated in 1969-74 the 5-year relapse-free survival and survival rates were 78% and 81%, respectively, whereas...
In an unselected series of 49 children with Wilms' tumour treated in 1969-74 the 5-year relapse-free survival and survival rates were 78% and 81%, respectively, whereas in the series of children treated in 1963-68 the corresponding rates were 49% and 70%. The significant improvement in the relapse-free survival rate was a result of adjuvant treatment with actinomycin D and vincristine (AMD + VCR), which, in some patients, eradicated occult metastatic disease. In the treatment of lung metastases the combination of whole-lung irradiation and maintained chemotherapy with AMD + VCR proved excessively toxic: in 5 of 11 patients acute diffuse pneumonitis developed, and it was fatal in 3. Adjuvant AMD + VCR therapy is advocated in all patients with Wilms' tumour except children less than 12 months old with a tumour of moderate size, limited to the kidney and completely resectable.
Topics: Child; Child, Preschool; Dactinomycin; Drug Therapy, Combination; Female; Humans; Kidney Neoplasms; Male; Neoplasm Metastasis; Pneumonia; Recurrence; Remission, Spontaneous; Vincristine; Wilms Tumor
PubMed: 179690
DOI: No ID Found -
Journal of Bacteriology Sep 1988Recent studies have suggested that the onset of synthesis of actinomycin D in Streptomyces parvulus is due to a release from L-glutamate catabolic repression. In the...
Metabolic regulation in Streptomyces parvulus during actinomycin D synthesis, studied with 13C- and 15N-labeled precursors by 13C and 15N nuclear magnetic resonance spectroscopy and by gas chromatography-mass spectrometry.
Recent studies have suggested that the onset of synthesis of actinomycin D in Streptomyces parvulus is due to a release from L-glutamate catabolic repression. In the present investigation we showed that S. parvulus has the capacity to maintain high levels of intracellular glutamate during the synthesis of actinomycin D. The results seem contradictory, since actinomycin D synthesis cannot start before a release from L-glutamate catabolic repression, but a relatively high intracellular pool of glutamate is needed for the synthesis of actinomycin D. Utilizing different labeled precursors, D-[U-13C]fructose and 13C- and 15N-labeled L-glutamate, and nuclear magnetic resonance techniques, we showed that carbon atoms of an intracellular glutamate pool of S. parvulus were not derived biosynthetically from the culture medium glutamate source but rather from D-fructose catabolism. A new intracellular pyrimidine derivative whose nitrogen and carbon skeletons were derived from exogenous L-glutamate was obtained as the main glutamate metabolite. Another new pyrimidine derivative that had a significantly reduced intracellular mobility and that was derived from D-fructose catabolism was identified in the cell extracts of S. parvulus during actinomycin D synthesis. These pyrimidine derivatives may serve as a nitrogen store for actinomycin D synthesis. In the present study, the N-trimethyl group of a choline derivative was observed by 13C nuclear magnetic resonance spectroscopy in growing S. parvulus cells. The choline group, as well as the N-methyl groups of sarcosine, N-methyl-valine, and the methyl groups of an actinomycin D chromophore, arose from D-fructose catabolism. The 13C enrichments found in the peptide moieties of actinomycin D were in accordance with a mechanism of actinomycin D synthesis from L-glutamate and D-fructose.
Topics: Chemical Phenomena; Chemistry; Dactinomycin; Fructose; Gas Chromatography-Mass Spectrometry; Glutamates; Magnetic Resonance Spectroscopy; Streptomyces
PubMed: 3410824
DOI: 10.1128/jb.170.9.4055-4064.1988 -
British Journal of Cancer Dec 2013Side effects of chemotherapy are a major impediment in the treatment of cancer. Cyclotherapy is an emerging therapeutic strategy for protecting normal cells from the... (Review)
Review
Side effects of chemotherapy are a major impediment in the treatment of cancer. Cyclotherapy is an emerging therapeutic strategy for protecting normal cells from the side effects of chemotherapy. Low, non-genotoxic doses of known p53 activators can be used to induce p53-dependent cell cycle arrest in normal cells bearing wild-type p53. This cytostatic effect of p53 can protect normal cells from the toxicity of S- or M-phase poisons. Here, we have reviewed existing cyclotherapy regimens using two well-known p53 activators, nutlin-3 and actinomycin D. We have highlighted an exemplar clinical perspective for cyclotherapy in breast cancer. The recent development of novel stapled peptides as activators of p53 without the corresponding cytotoxicity holds great promise for cyclotherapy to enhance the therapeutic window of existing chemotherapy drugs.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Breast Neoplasms; Cell Growth Processes; Cell Line, Tumor; Dactinomycin; Female; Genome; Humans; Imidazoles; Phosphorylation; Piperazines; Tumor Suppressor Protein p53
PubMed: 24231949
DOI: 10.1038/bjc.2013.702 -
British Journal of Clinical Pharmacology May 2016Use of the anti-tumour antibiotic actinomycin D is associated with development of hepatotoxicity, particularly in young children. A paucity of actinomycin D...
AIMS
Use of the anti-tumour antibiotic actinomycin D is associated with development of hepatotoxicity, particularly in young children. A paucity of actinomycin D pharmacokinetic data make it challenging to develop a sound rationale for defining dosing regimens in younger patients. The study aim was to develop a physiologically based pharmacokinetic (PBPK) model using a combination of data from the literature and generated from experimental analyses.
METHODS
Assays to determine actinomycin D Log P, blood:plasma partition ratio and ABCB1 kinetics were conducted. These data were combined with physiochemical properties sourced from the literature to generate a compound file for use within the modelling-simulation software Simcyp (version 14 release 1). For simulation, information was taken from two datasets, one from 117 patients under the age of 21 and one from 20 patients aged 16-48.
RESULTS
The final model incorporated clinical renal and biliary clearance data and an additional systemic clearance value. The mean AUC0-26h of simulated subjects was within 1.25-fold of the observed AUC0-26h (84 ng h ml(-1) simulated vs. 93 ng h ml(-1) observed). For the younger age ranges, AUC predictions were within two-fold of observed values, with simulated data from six of the eight age/dose ranges falling within 15% of observed data. Simulated values for actinomycin D AUC0-26h and clearance in infants aged 0-12 months ranged from 104 to 115 ng h ml(-1) and 3.5-3.8 l h(-1) , respectively.
CONCLUSIONS
The model has potential utility for prediction of actinomycin D exposure in younger patients and may help guide future dosing. However, additional independent data from neonates and infants is needed for further validation. Physiological differences between paediatric cancer patients and healthy children also need to be further characterized and incorporated into PBPK models.
Topics: ATP Binding Cassette Transporter, Subfamily B; Adolescent; Adult; Animals; Antibiotics, Antineoplastic; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Cohort Studies; Computer Simulation; Dactinomycin; Dogs; Female; Humans; Infant; Madin Darby Canine Kidney Cells; Male; Models, Biological; Neoplasms; Young Adult
PubMed: 26727248
DOI: 10.1111/bcp.12878 -
Marine Drugs Aug 2020The high toxicity of actinomycin D (Act D) severely limits its use as a first-line chemotherapeutic agent in the clinic. Actinomycin V (Act V), an analog of Act D,... (Comparative Study)
Comparative Study
The high toxicity of actinomycin D (Act D) severely limits its use as a first-line chemotherapeutic agent in the clinic. Actinomycin V (Act V), an analog of Act D, exhibited strong anticancer activity in our previous studies. Here, we provide evidence that Act V has less hepatorenal toxicity than Act D in vitro and in vivo, associated with the reactive oxygen species (ROS) pathway. Compared to Act D, Act V exhibited considerably stronger sensitivity for cancer cells and less toxicity to human normal liver LO-2 and human embryonic kidney 293T cells using the MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assay. Notably, Act V caused less damage to both the liver and kidney than Act D in vivo, indicated by organ to body weight ratios, as well as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and serum creatinine (Scr) levels. Further experiments showed that the ROS pathway is involved in Act V-induced hepatorenal toxicity. Act V generates ROS and accumulates malondialdehyde (MDA), reducing levels of superoxide dismutase (SOD) and glutathione (GSH) in LO-2 and 293T cells. These findings indicate that Act V induces less hepatorenal toxicity than Act D in vitro and in vivo and merits further development as a potential therapeutic agent for the treatment of cancer.
Topics: Animals; Antibiotics, Antineoplastic; Chemical and Drug Induced Liver Injury; Dactinomycin; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Kidney; Kidney Diseases; Lipid Peroxidation; Liver; Male; Mice; Oxidative Stress; Reactive Oxygen Species
PubMed: 32824227
DOI: 10.3390/md18080428 -
Marine Drugs Oct 2016An extract prepared from the culture of a marine-derived actinomycete sp. ZZ338 was found to have significant antimicrobial and antiproliferative activities. A chemical...
An extract prepared from the culture of a marine-derived actinomycete sp. ZZ338 was found to have significant antimicrobial and antiproliferative activities. A chemical investigation of this active extract resulted in the isolation of three known bioactive actinomycins (-) and two new metabolites ( and ). The structures of the isolated compounds were identified as actinomycins D (), V (), X (), 2-acetylamino-3-hydroxyl-4-methyl-benzoic acid methyl ester (), and -1-(4-methylaminophenylmethyl)-2-oxo-propyl acetamide () based on their nuclear magnetic resonance (NMR) and high resolution electrospray ionization mass spectroscopy (HRESIMS) data as well as their optical rotation. This class of new compound had never before been found from a natural resource. Three known actinomycins showed activities in inhibiting the proliferation of glioma cells and the growth of methicillin-resistant , , and and are responsible for the activity of the crude extract. Actinomycin D () was also found to downregulate several glioma metabolic enzymes of glycolysis, glutaminolysis, and lipogenesis, suggesting that targeting multiple tumor metabolic regulators might be a new anti-glioma mechanism of actinomycin D. This is the first report of such a possible mechanism for the class of actinomycins.
Topics: Animals; Anti-Infective Agents; Antineoplastic Agents; Candida albicans; Dactinomycin; Drug Screening Assays, Antitumor; Escherichia coli; Humans; Inhibitory Concentration 50; Oceans and Seas; Rats; Staphylococcus aureus; Streptomyces; Structure-Activity Relationship; Tumor Cells, Cultured
PubMed: 27727167
DOI: 10.3390/md14100181 -
Nucleic Acids Research Dec 2018A multi-technique approach, combining circular dichroism spectroscopy, ultraviolet resonance Raman spectroscopy and small angle scattering techniques, has been deployed...
A multi-technique approach, combining circular dichroism spectroscopy, ultraviolet resonance Raman spectroscopy and small angle scattering techniques, has been deployed to elucidate how the structural features of the human telomeric G-quadruplex d[A(GGGTTA)3GGG] (Tel22) change upon thermal unfolding. The system is studied both in the free form and when it is bound to Actinomycin D (ActD), an anticancer ligand with remarkable conformational flexibility. We find that at room temperature binding of Tel22 with ActD involves end-stacking upon the terminal G-tetrad. Structural evidence for drug-driven dimerization of a significant fraction of the G-quadruplexes is provided. When the temperature is raised, both free and bound Tel22 undergo melting through a multi-state process. We show that in the intermediate states of Tel22 the conformational equilibrium is shifted toward the (3+1) hybrid-type, while a parallel structure is promoted in the complex. The unfolded state of the free Tel22 is consistent with a self-avoiding random-coil conformation, whereas the high-temperature state of the complex is observed to assume a quite compact form. Such an unprecedented high-temperature arrangement is caused by the persistent interaction between Tel22 and ActD, which stabilizes compact conformations even in the presence of large thermal structural fluctuations.
Topics: Anti-Bacterial Agents; Antineoplastic Agents; Binding Sites; Dactinomycin; Dimerization; G-Quadruplexes; Hot Temperature; Humans; Kinetics; Ligands; Models, Molecular; Nucleic Acid Denaturation; Telomere; Thermodynamics
PubMed: 30407585
DOI: 10.1093/nar/gky1092