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Cancer Discovery Dec 2021Acute myeloid leukemia (AML) pathogenesis often involves a mutation in the NPM1 nucleolar chaperone, but the bases for its transforming properties and overall...
UNLABELLED
Acute myeloid leukemia (AML) pathogenesis often involves a mutation in the NPM1 nucleolar chaperone, but the bases for its transforming properties and overall association with favorable therapeutic responses remain incompletely understood. Here we demonstrate that an oncogenic mutant form of NPM1 (NPM1c) impairs mitochondrial function. NPM1c also hampers formation of promyelocytic leukemia (PML) nuclear bodies (NB), which are regulators of mitochondrial fitness and key senescence effectors. Actinomycin D (ActD), an antibiotic with unambiguous clinical efficacy in relapsed/refractory NPM1c-AMLs, targets these primed mitochondria, releasing mitochondrial DNA, activating cyclic GMP-AMP synthase signaling, and boosting reactive oxygen species (ROS) production. The latter restore PML NB formation to drive TP53 activation and senescence of NPM1c-AML cells. In several models, dual targeting of mitochondria by venetoclax and ActD synergized to clear AML and prolong survival through targeting of PML. Our studies reveal an unexpected role for mitochondria downstream of NPM1c and implicate a mitochondrial/ROS/PML/TP53 senescence pathway as an effector of ActD-based therapies.
SIGNIFICANCE
ActD induces complete remissions in NPM1-mutant AMLs. We found that NPM1c affects mitochondrial biogenesis and PML NBs. ActD targets mitochondria, yielding ROS which enforce PML NB biogenesis and restore senescence. Dual targeting of mitochondria with ActD and venetoclax sharply potentiates their anti-AML activities in vivo. This article is highlighted in the In This Issue feature, p. 2945.
Topics: Dactinomycin; Humans; Leukemia, Myeloid, Acute; Mitochondria; Nuclear Proteins; Nucleophosmin
PubMed: 34301789
DOI: 10.1158/2159-8290.CD-21-0177 -
Cancer Chemotherapy and Pharmacology Aug 2021Actinomycin-D and vincristine are cytotoxic drugs commonly used to treat cancers in children. This prospective study assessed pharmacokinetic variability and toxicity of...
Actinomycin-D and vincristine are cytotoxic drugs commonly used to treat cancers in children. This prospective study assessed pharmacokinetic variability and toxicity of these drugs in children. Blood samples were collected in 158 patients. Actinomycin-D or vincristine concentrations were quantified using high-performance liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated using non-compartmental methods. Target toxicities were collected prospectively. Actinomycin-D pharmacokinetics (n = 52 patients) were highly variable. The median (coefficient of variation, CV%) area under the concentration-time curve (AUC) was 332 ng/mL·h. (110%); clearance was 4.6 L/h/m (90%); half-life was 25 h (60%). No patient met the defined criteria for myelosuppression. In multivariate analysis, none of the demographic nor pharmacokinetic parameters was predictors of acute hepatotoxicity. Vincristine pharmacokinetics (n = 132 patients) demonstrated substantial variability. The median (CV%) AUC was 78 ng/mL·h (98%); clearance was 17.2 L/h/m (67%); half-life was 14.6 h (73%). In multivariate analysis, the effect of increasing age for a given BSA was an increase in neuropathy while the effect of increasing BSA for a given age was a decrease in neuropathy. Conclusion: Pharmacokinetics of both drugs were highly variable. For actinomycin-D, there was no correlation between demographic or pharmacokinetic parameters and target toxicities. For vincristine, the correlations of age and BSA and neuropathy are confounded by the correlation between age and BSA in children and the ability to ascertain neuropathy in infants. Variability may be attributed to dose reductions and capped doses for both drugs. Investigation of BSA-based dosing in young children is warranted to decrease variability of exposure.
Topics: Adolescent; Antineoplastic Agents; Area Under Curve; Child; Child, Preschool; Dactinomycin; Female; Half-Life; Humans; Infant; Male; Neoplasms; Prospective Studies; Vincristine
PubMed: 34023919
DOI: 10.1007/s00280-021-04295-1 -
PeerJ 2023Multidrug-resistant tuberculosis (MDR-TB) is one of the world's most devastating contagious diseases and is caused by the MDR- (MDR-Mtb) bacteria. It is therefore...
BACKGROUND
Multidrug-resistant tuberculosis (MDR-TB) is one of the world's most devastating contagious diseases and is caused by the MDR- (MDR-Mtb) bacteria. It is therefore essential to identify novel anti-TB drug candidates and target proteins to treat MDR-TB. Here, and studies were used to investigate the anti-TB potential of two newly sourced actinomycins, actinomycin-X (act-X) and actinomycin-D (act-D), from the strain UKAQ_23 (isolated from the Jubail industrial city of Saudi Arabia).
METHODS
The anti-TB activity of the isolated actinomycins was assessed using the Mtb H37Ra, (BCG), and Mtb H37Rv bacterial strains, using the Microplate Alamar Blue Assay (MABA) method. molecular docking studies were conducted using sixteen anti-TB drug target proteins using the AutoDock Vina 1.1.2 tool. The molecular dynamics (MD) simulations for both actinomycins were then performed with the most suitable target proteins, using the GROningen MAchine For Chemical Simulations (GROMACS) simulation software (GROMACS 2020.4), with the Chemistry at HARvard Macromolecular Mechanics 36m (CHARMM36m) forcefield for proteins and the CHARMM General Force Field (CGenFF) for ligands.
RESULTS
results for the Mtb H37Ra, BCG, and Mtb H37Rv strains showed that act-X had minimum inhibitory concentration (MIC) values of 1.56 ± 0.0, 1.56 ± 0.0, and 2.64 ± 0.07 µg/mL and act-D had MIC values of 1.56 ± 0.0, 1.56 ± 0.0, and 1.80 ± 0.24 µg/mL respectively. The molecular docking results showed that protein kinase PknB was the preferred target for both actinomycins, while KasA and pantothenate synthetase were the least preferred targets for act-Xand act-D respectively. The molecular dynamics (MD) results demonstrated that act-X and act-D remained stable inside the binding region of PknB throughout the simulation period. The MM/GBSA (Molecular Mechanics/Generalized Born Surface Area) binding energy calculations showed that act-X was more potent than act-D.
CONCLUSION
In conclusion, our results suggest that both actinomycins X and D are highly potent anti-TB drug candidates. We show that act-Xis better able to antagonistically interact with the protein kinase PknB target than act-D, and thus has more potential as a new anti-TB drug candidate.
Topics: Humans; Antitubercular Agents; BCG Vaccine; Dactinomycin; Molecular Docking Simulation; Protein Kinases; Tuberculosis, Multidrug-Resistant
PubMed: 36935926
DOI: 10.7717/peerj.14502 -
The Cochrane Database of Systematic... Jun 2016This is the second update of a Cochrane review that was first published in 2009, Issue 1, . Gestational trophoblastic neoplasia (GTN) is a rare but curable disease... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This is the second update of a Cochrane review that was first published in 2009, Issue 1, . Gestational trophoblastic neoplasia (GTN) is a rare but curable disease arising in the fetal chorion during pregnancy. Most women with low-risk GTN will be cured by evacuation of the uterus with or without single-agent chemotherapy. However, chemotherapy regimens vary between treatment centres worldwide and the comparable benefits and risks of these different regimens are unclear.
OBJECTIVES
To determine the efficacy and safety of first-line chemotherapy in the treatment of low-risk GTN.
SEARCH METHODS
We electronically searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase in September 2008, February 2012, and January 2016. In addition, we searched online trial registers for protocols and ongoing trials.
SELECTION CRITERIA
For the original review, we included randomised controlled trials (RCTs), quasi-RCTs and non-RCTs that compared first-line chemotherapy for the treatment of low-risk GTN. For this updated versions of the review, we included only RCTs.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed studies for inclusion and extracted data to a pre-designed data extraction form. Meta-analysis was performed using the random-effects model.
MAIN RESULTS
We included seven RCTs (667 women) in this updated review. Most studies were at a low or moderate risk of bias and all compared methotrexate with actinomycin D. Three studies compared weekly intramuscular (IM) methotrexate with bi-weekly pulsed intravenous (IV) actinomycin D (393 women), one study compared five-day IM methotrexate with bi-weekly pulsed IV actinomycin D (75 women), one study compared eight-day IM methotrexate-folinic acid (MTX-FA) with five-day IV actinomycin D (49 women), and one study compared eight-day IM MTX-FA with bi-weekly pulsed IV actinomycin D. One study contributed no data. Moderate-certainty evidence indicates that actinomycin D is probably more likely to lead to primary cure than methotrexate (risk ratio (RR) 0.65, 95% confidence interval (CI) 0.57 to 0.75; six trials, 577 participants; I(2) = 26%), and first-line methotrexate treatment is probably more likely to fail than actinomycin D treatment (RR 3.55, 95% CI 1.81 to 6.95; six trials, 577 participants; I(2) = 61%; moderate-certainty evidence) Low-certainty evidence suggests that there may be little or no difference between methotrexate and actinomycin D treatment with respect to nausea (four studies, 466 women; RR 0.61, 95% CI 0.29 to 1.26) or any of the other individual side-effects reported, although data for all of these outcomes were insufficient and too inconsistent to be conclusive. Low-certainty evidence suggests that there may be little or no difference in the risk of severe adverse events (SAEs) between the groups overall (five studies, 515 women; RR 0.35, 95% CI 0.08 to 1.66; I² = 60%); however, the direction of effect favours methotrexate and more evidence is needed. Furthermore, evidence from subgroup analyses suggests that actinomycin D may be associated with a greater risk of SAEs than methotrexate (low-certainty evidence). We found no evidence on the effect of these treatments on future fertility.
AUTHORS' CONCLUSIONS
Actinomycin D is probably more likely to achieve a primary cure in women with low-risk GTN, and less likely to result in treatment failure, than a methotrexate regimen. There may be little or no difference between the pulsed actinomycin D regimen and the methotrexate regimen with regard to side-effects. However, actinomycin D may be associated with a greater risk of severe adverse events (SAEs) than a methotrexate regimen. Higher-certainty evidence is still needed on treating low-risk GTN and the four ongoing trials are likely to make a significant contribution to this field. Given the variety of treatment regimens, findings from these trials could facilitate a network meta-analysis in the next version of this review to help women and clinicians determine the best treatment options for low-risk GTN.
Topics: Antineoplastic Agents; Case-Control Studies; Cohort Studies; Dactinomycin; Drug Administration Schedule; Female; Gestational Trophoblastic Disease; Humans; Leucovorin; Methotrexate; Pregnancy; Randomized Controlled Trials as Topic; Risk; Vitamin B Complex
PubMed: 27281496
DOI: 10.1002/14651858.CD007102.pub4 -
Scientific Reports Jul 2021Streptomyces smyrnaeus UKAQ_23, isolated from the mangrove-sediment, collected from Jubail,Saudi Arabia, exhibited substantial antimicrobial activity against...
Isolation, characterization, anti-MRSA evaluation, and in-silico multi-target anti-microbial validations of actinomycin X and actinomycin D produced by novel Streptomyces smyrnaeus UKAQ_23.
Streptomyces smyrnaeus UKAQ_23, isolated from the mangrove-sediment, collected from Jubail,Saudi Arabia, exhibited substantial antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA), including non-MRSA Gram-positive test bacteria. The novel isolate, under laboratory-scale conditions, produced the highest yield (561.3 ± 0.3 mg/kg fermented agar) of antimicrobial compounds in modified ISP-4 agar at pH 6.5, temperature 35 °C, inoculum 5% v/w, agar 1.5% w/v, and an incubation period of 7 days. The two major compounds, K and K, were isolated from fermented medium and identified as Actinomycin X and Actinomycin D, respectively, based on their structural analysis. The antimicrobial screening showed that Actinomycin X had the highest antimicrobial activity compared to Actinomycin D, and the actinomycins-mixture (X:D, 1:1, w/w) against MRSA and non-MRSA Gram-positive test bacteria, at 5 µg/disc concentrations. The MIC of Actinomycin X ranged from 1.56-12.5 µg/ml for non-MRSA and 3.125-12.5 µg/ml for MRSA test bacteria. An in-silico molecular docking demonstrated isoleucyl tRNA synthetase as the most-favored antimicrobial protein target for both actinomycins, X and D, while the penicillin-binding protein-1a, was the least-favorable target-protein. In conclusion, Streptomyces smyrnaeus UKAQ_23 emerged as a promising source of Actinomycin X with the potential to be scaled up for industrial production, which could benefit the pharmaceutical industry.
Topics: Anti-Bacterial Agents; Computer Simulation; Culture Media; Dactinomycin; Drug Evaluation, Preclinical; Fermentation; Magnetic Resonance Spectroscopy; Mass Spectrometry; Methicillin-Resistant Staphylococcus aureus; Molecular Docking Simulation; Molecular Structure; Phylogeny; Streptomyces
PubMed: 34267232
DOI: 10.1038/s41598-021-93285-7 -
Scientific Reports Feb 2022Streptomycetes are major producers of bioactive natural products, including the majority of the naturally produced antibiotics. While much of the low-hanging fruit has...
Streptomycetes are major producers of bioactive natural products, including the majority of the naturally produced antibiotics. While much of the low-hanging fruit has been discovered, it is predicted that less than 5% of the chemical space of natural products has been mined. Here, we describe the discovery of the novel actinomycins L and L produced by Streptomyces sp. MBT27, via application of metabolic analysis and molecular networking. Actinomycins L and L are diastereomers, and the structure of actinomycin L was resolved using NMR and single crystal X-ray crystallography. Actinomycin L is formed via spirolinkage of anthranilamide to the 4-oxoproline moiety of actinomycin X prior to the condensation of the actinomycin halves. Such a structural feature has not previously been identified in naturally occurring actinomycins. Adding anthranilamide to cultures of the actinomycin X producer Streptomyces antibioticus, which has the same biosynthetic gene cluster as Streptomyces sp. MBT27, resulted in the production of actinomycin L. This supports a biosynthetic pathway whereby actinomycin L is produced from two distinct metabolic routes, namely those for actinomycin X and for anthranilamide. Actinomycins L and L showed significant antimicrobial activity against Gram-positive bacteria. Our work shows how new molecules can still be identified even in the oldest of natural product families.
Topics: Anti-Bacterial Agents; Biological Products; Biosynthetic Pathways; Dactinomycin; Gram-Positive Bacteria; Humans; Streptomyces antibioticus; Streptomycetaceae; ortho-Aminobenzoates
PubMed: 35181725
DOI: 10.1038/s41598-022-06736-0 -
Marine Drugs Jan 2022Methicillin-resistant (MRSA) is highly concerning as a principal infection pathogen. The investigation of higher effective natural anti-MRSA agents from marine has led...
Methicillin-resistant (MRSA) is highly concerning as a principal infection pathogen. The investigation of higher effective natural anti-MRSA agents from marine has led to the isolation of actinomycin D, that showed potential anti-MRSA activity with MIC and MBC values of 1 and 8 μg/mL, respectively. Proteomics-metabolomics analysis further demonstrated a total of 261 differential proteins and 144 differential metabolites induced by actinomycin D in MRSA, and the co-mapped correlation network of omics, indicated that actinomycin D induced the metabolism pathway of producing the antibiotic sensitivity in MRSA. Furthermore, the mRNA expression levels of the genes , , , , and related to the key differential proteins were down-regulated measured by qRT-PCR. Molecular docking predicted that actinomycin D was bound to the targets of the two key differential proteins AcnA and Icd by hydrogen bonds and interacted with multiple amino acid residues of the proteins. Thus, these findings will provide a basic understanding to further investigation of actinomycin D as a potential anti-MRSA agent.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Dactinomycin; Metabolomics; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Molecular Docking Simulation; Proteomics; Streptomyces
PubMed: 35200643
DOI: 10.3390/md20020114 -
Medicine Nov 20225-Fluorouracil (5-FU) and actinomycin D (ActD) are often used in chemotherapy for various cancers. Side effects are more common in bone marrow suppression, liver... (Review)
Review
RATIONALE
5-Fluorouracil (5-FU) and actinomycin D (ActD) are often used in chemotherapy for various cancers. Side effects are more common in bone marrow suppression, liver function impairment, and gastrointestinal responses. Skin effects are rare and easy to be ignored by doctors and patients, which can lead to life-threatening consequence.
PATIENT CONCERNS
We reported a 45-year-old woman patient developed skin erythema and fingernail belt in chemotherapy of 5-FU and ActD.
DIAGNOSIS
Erythema multiforme drug eruption.
INTERVENTIONS
Laboratory tests including blood and urine routine, liver and kidney function, electrolytes and coagulation function and close observation.
OUTCOMES
The rash was gone and the nail change returned.
LESSONS
Delays in diagnosis or treatment may lead to serious consequence. We should pay attention to the dosage of 5-FU and ActD, monitor adverse reactions strictly, to reduce occurrence of skin malignant events.
Topics: Female; Pregnancy; Humans; Middle Aged; Dactinomycin; Hydatidiform Mole, Invasive; Fluorouracil; Erythema Multiforme; Drug Eruptions; Uterine Neoplasms
PubMed: 36451432
DOI: 10.1097/MD.0000000000031678 -
Proceedings of the National Academy of... Aug 1985Recent advances in understanding how actinomycin binds to DNA have suggested its mechanism of action. Actinomycin binds to a premelted DNA conformation present within...
Recent advances in understanding how actinomycin binds to DNA have suggested its mechanism of action. Actinomycin binds to a premelted DNA conformation present within the transcriptional complex. This immobilizes the complex, interfering with the elongation of growing RNA chains. The model has a number of implications for understanding RNA synthesis.
Topics: Animals; Cell Nucleolus; DNA-Directed RNA Polymerases; Dactinomycin; Microscopy, Electron; Models, Molecular; Molecular Conformation; Nucleic Acid Conformation; Nucleic Acid Denaturation; Transcription, Genetic
PubMed: 2410919
DOI: 10.1073/pnas.82.16.5328 -
Nucleic Acids Research May 2023Combination cancer chemotherapy is one of the most useful treatment methods to achieve a synergistic effect and reduce the toxicity of dosing with a single drug. Here,...
Combination cancer chemotherapy is one of the most useful treatment methods to achieve a synergistic effect and reduce the toxicity of dosing with a single drug. Here, we use a combination of two well-established anticancer DNA intercalators, actinomycin D (ActD) and echinomycin (Echi), to screen their binding capabilities with DNA duplexes containing different mismatches embedded within Watson-Crick base-pairs. We have found that combining ActD and Echi preferentially stabilised thymine-related T:T mismatches. The enhanced stability of the DNA duplex-drug complexes is mainly due to the cooperative binding of the two drugs to the mismatch duplex, with many stacking interactions between the two different drug molecules. Since the repair of thymine-related mismatches is less efficient in mismatch repair (MMR)-deficient cancer cells, we have also demonstrated that the combination of ActD and Echi exhibits enhanced synergistic effects against MMR-deficient HCT116 cells and synergy is maintained in a MMR-related MLH1 gene knockdown in SW620 cells. We further accessed the clinical potential of the two-drug combination approach with a xenograft mouse model of a colorectal MMR-deficient cancer, which has resulted in a significant synergistic anti-tumour effect. The current study provides a novel approach for the development of combination chemotherapy for the treatment of cancers related to DNA-mismatches.
Topics: Humans; Animals; Mice; Dactinomycin; Echinomycin; Thymine; Base Sequence; Binding Sites; Nucleic Acid Conformation; DNA; Colorectal Neoplasms
PubMed: 36919604
DOI: 10.1093/nar/gkad156