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Molecules (Basel, Switzerland) Jan 2021Amsacrine, an anticancer drug first synthesised in 1970 by Professor Cain and colleagues, showed excellent preclinical activity and underwent clinical trial in 1978... (Review)
Review
Amsacrine, an anticancer drug first synthesised in 1970 by Professor Cain and colleagues, showed excellent preclinical activity and underwent clinical trial in 1978 under the auspices of the US National Cancer Institute, showing activity against acute lymphoblastic leukaemia. In 1984, the enzyme DNA topoisomerase II was identified as a molecular target for amsacrine, acting to poison this enzyme and to induce DNA double-strand breaks. One of the main challenges in the 1980s was to determine whether amsacrine analogues could be developed with activity against solid tumours. A multidisciplinary team was assembled in Auckland, and Professor Denny played a leading role in this approach. Among a large number of drugs developed in the programme, -[2-(dimethylamino)-ethyl]-acridine-4-carboxamide (DACA), first synthesised by Professor Denny, showed excellent activity against a mouse lung adenocarcinoma. It underwent clinical trial, but dose escalation was prevented by ion channel toxicity. Subsequent work led to the DACA derivative SN 28049, which had increased potency and reduced ion channel toxicity. Mode of action studies suggested that both amsacrine and DACA target the enzyme DNA topoisomerase II but with a different balance of cellular consequences. As primarily a topoisomerase II poison, amsacrine acts to turn the enzyme into a DNA-damaging agent. As primarily topoisomerase II catalytic inhibitors, DACA and SN 28049 act to inhibit the segregation of daughter chromatids during anaphase. The balance between these two actions, one cell cycle phase specific and the other nonspecific, together with pharmacokinetic, cytokinetic and immunogenic considerations, provides links between the actions of acridine derivatives and anthracyclines such as doxorubicin. They also provide insights into the action of cytotoxic DNA-binding drugs.
Topics: Adenocarcinoma of Lung; Amsacrine; Anaphase; Animals; Antineoplastic Agents; Chromatids; Chromosome Segregation; DNA Topoisomerases, Type II; DNA, Neoplasm; History, 20th Century; History, 21st Century; Humans; Lung Neoplasms; Mice; Naphthyridines; Neoplasm Proteins; Topoisomerase II Inhibitors
PubMed: 33494466
DOI: 10.3390/molecules26030552 -
Molecules (Basel, Switzerland) Dec 2022This review summarized the current breakthroughs in the chemistry of acridines as anti-cancer agents, including new structural and biologically active acridine... (Review)
Review
This review summarized the current breakthroughs in the chemistry of acridines as anti-cancer agents, including new structural and biologically active acridine attributes. Acridine derivatives are a class of compounds that are being extensively researched as potential anti-cancer drugs. Acridines are well-known for their high cytotoxic activity; however, their clinical application is restricted or even excluded as a result of side effects. The photocytotoxicity of propyl acridine acts against leukaemia cell lines, with C1748 being a promising anti-tumour drug against UDP-UGT's. CK0403 is reported in breast cancer treatment and is more potent than CK0402 against estrogen receptor-negative HER2. Acridine platinum (Pt) complexes have shown specificity on the evaluated DNA sequences; 9-anilinoacridine core, which intercalates DNA, and a methyl triazene DNA-methylating moiety were also studied. Acridine thiourea gold and acridinone derivatives act against cell lines such as MDA-MB-231, SK-BR-3, and MCF-7. Benzimidazole acridine compounds demonstrated cytotoxic activity against Dual Topo and PARP-1. Quinacrine, thiazacridine, and azacridine are reported as anti-cancer agents, which have been reported in the previous decade and were addressed in this review article.
Topics: Humans; Female; Antineoplastic Agents; Cell Line; Intercalating Agents; DNA; Breast Neoplasms; Acridines; Cell Line, Tumor
PubMed: 36615391
DOI: 10.3390/molecules28010193 -
Journal of Applied Toxicology : JAT Apr 2022The potential of acridines (amsacrine) as a topoisomerase II inhibitor or poison was first discovered in 1984, and since then, a considerable number of acridine... (Review)
Review
The potential of acridines (amsacrine) as a topoisomerase II inhibitor or poison was first discovered in 1984, and since then, a considerable number of acridine derivatives have been tested as topoisomerase inhibitors/poisons, containing different substituents on the acridine chromophore. This review will discuss a series of studies published over the course of the last decade, which have investigated various novel acridine derivatives against topoisomerase II activity.
Topics: Acridines; Amsacrine; Antineoplastic Agents; DNA Topoisomerases, Type II; Poisons
PubMed: 34514603
DOI: 10.1002/jat.4238 -
Journal of Applied Toxicology : JAT Jan 2021Heterocycles have long been the focus of intensive study in attempts to develop novel therapeutic compounds, and acridine, a polynuclear nitrogen molecule containing a... (Review)
Review
Heterocycles have long been the focus of intensive study in attempts to develop novel therapeutic compounds, and acridine, a polynuclear nitrogen molecule containing a heterocycle, has attracted a considerable amount of scientific attention. Acridine derivatives have been studied in detail and have been found to possess multitarget properties, which inhibit topoisomerase enzymes that regulate topological changes in DNA and interfere with the essential biological function of DNA. This article describes some recent advancements in the field of new 9-substituted acridine heterocyclic agents and describes both the structure and the structure-activity relationship of the most promising molecules. The article will also present the IC values of the novel derivatives against various human cancer cell lines. The mini review also investigates the topoisomerase inhibition and antibacterial and antimalarial activity of these polycyclic aromatic derivatives.
Topics: Acridines; Anti-Bacterial Agents; Antimalarials; Antineoplastic Agents; Humans; Structure-Activity Relationship; Topoisomerase II Inhibitors; Tumor Cells, Cultured
PubMed: 32969520
DOI: 10.1002/jat.4072 -
The Journal of Infectious Diseases May 2022Limited evidence exists on efficacy and tolerability of quinacrine for nitroimidazole-refractory giardiasis.
BACKGROUND
Limited evidence exists on efficacy and tolerability of quinacrine for nitroimidazole-refractory giardiasis.
METHODS
Nitroimidazole-refractory giardiasis cases, defined as microbiologically (microscopy and/or PCR) confirmed treatment failure after 2 courses, during 2008-2020, were retrospectively identified.
RESULTS
Of 87 patients, 54 (62%) had visited India. Quinacrine was used in 54 (62%); 51 received monotherapy and 3 combined with metronidazole. Only 3 had positive stool samples with persisting symptoms after quinacrine treatment (94% parasitological efficacy) and all were cured after a second treatment. One (1.9%) had mild adverse effects recorded.
CONCLUSIONS
Quinacrine is an effective treatment for nitroimidazole-refractory giardiasis with good tolerability.
Topics: Antiprotozoal Agents; Giardiasis; Humans; Metronidazole; Nitroimidazoles; Quinacrine; Retrospective Studies
PubMed: 34036328
DOI: 10.1093/infdis/jiab287 -
Molecular Neurodegeneration Dec 2022Microglia regulate the response to injury and disease in the brain and spinal cord. In white matter diseases microglia may cause demyelination. However, how microglia...
BACKGROUND
Microglia regulate the response to injury and disease in the brain and spinal cord. In white matter diseases microglia may cause demyelination. However, how microglia respond and regulate demyelination is not fully understood.
METHODS
To understand how microglia respond during demyelination, we fed mice cuprizone-a potent demyelinating agent-and assessed the dynamics of genetically fate-mapped microglia. We then used single-cell RNA sequencing to identify and track the microglial subpopulations that arise during demyelination. To understand how microglia contribute to the clearance of dead oligodendrocytes, we ablated microglia starting at the peak of cuprizone-induced cell death and used the viability dye acridine orange to monitor apoptotic and lytic cell morphologies after microglial ablation. Lastly, we treated serum-free primary microglial cultures to model distinct aspects of cuprizone-induced demyelination and assessed the response.
RESULTS
The cuprizone diet generated a robust microglial response by week 4 of the diet. Single-cell RNA sequencing at this time point revealed the presence of several cuprizone-associated microglia (CAM) clusters. These clusters expressed a transcriptomic signature indicative of cytokine regulation and reactive oxygen species production with altered lysosomal and metabolic changes consistent with ongoing phagocytosis. Using acridine orange to monitor apoptotic and lytic cell death after microglial ablation, we found that microglia preferentially phagocytose lytic carcasses. In culture, microglia exposed to lytic carcasses partially recapitulated the CAM state, suggesting that phagocytosis contributes to this distinct microglial state during cuprizone demyelination.
CONCLUSIONS
Microglia serve multiple roles during demyelination, yet their transcriptomic state resembles other neurodegenerative conditions. The phagocytosis of cellular debris is likely a universal cause for a common neurodegenerative microglial state.
Topics: Animals; Mice; Cuprizone; Microglia; Demyelinating Diseases; Transcriptome; Acridine Orange; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 36514132
DOI: 10.1186/s13024-022-00584-2 -
International Journal of Molecular... Jan 2023Swim-up selected human sperm were incubated with 7 ng F-neuroprostanes (F-NeuroPs) for 2 and 4 h. Sperm motility and membrane mitochondrial potential (MMP) were...
Swim-up selected human sperm were incubated with 7 ng F-neuroprostanes (F-NeuroPs) for 2 and 4 h. Sperm motility and membrane mitochondrial potential (MMP) were evaluated. The percentage of reacted acrosome was assessed by pisum sativum agglutinin (PSA). Chromatin integrity was detected using the acridine orange (AO) assay and localization of the ryanodine receptor was performed by immunofluorescence analysis. Sperm progressive motility ( = 0.02) and the percentage of sperm showing a strong MMP signal ( = 0.012) significantly increased after 2 h F-NeuroP incubation compared to control samples. The AO assay did not show differences in the percentage of sperm with dsDNA between treated or control samples. Meanwhile, a significantly higher number of sperm with reacted acrosomes was highlighted by PSA localization after 4 h F-NeuroP incubation. Finally, using an anti-ryanodine antibody, the immunofluorescence signal was differentially distributed at 2 and 4 h: a strong signal was evident in the midpiece and postacrosomal sheath (70% of sperm) at 2 h, whereas a dotted one appeared at 4 h (53% of sperm). A defined concentration of F-NeuroPs in seminal fluid may induce sperm capacitation via channel ions present in sperm cells, representing an aid during in vitro sperm preparation that may increase the positive outcome of assisted fertilization.
Topics: Humans; Male; Neuroprostanes; Sperm Motility; Seeds; Spermatozoa; Acrosome; Acridine Orange
PubMed: 36674450
DOI: 10.3390/ijms24020935 -
Analytical Biochemistry Dec 2022Eukaryotic cells are compartmentalized into membrane-bound organelles, allowing each organelle to maintain the specialized conditions needed for their specific...
Eukaryotic cells are compartmentalized into membrane-bound organelles, allowing each organelle to maintain the specialized conditions needed for their specific functions. One of the features that change between organelles is lumenal pH. In the endocytic and secretory pathways, lumenal pH is controlled by isoforms and concentration of the vacuolar-type H-ATPase (V-ATPase). In the endolysosomal pathway, copies of complete V-ATPase complexes accumulate as membranes mature from early endosomes to late endosomes and lysosomes. Thus, each compartment becomes more acidic as maturation proceeds. Lysosome acidification is essential for the breakdown of macromolecules delivered from endosomes as well as cargo from different autophagic pathways, and dysregulation of this process is linked to various diseases. Thus, it is important to understand the regulation of the V-ATPase. Here we describe a high-throughput method for screening inhibitors/activators of V-ATPase activity using Acridine Orange (AO) as a fluorescent reporter for acidified yeast vacuolar lysosomes. Through this method, the acidification of purified vacuoles can be measured in real-time in half-volume 96-well plates or a larger 384-well format. This not only reduces the cost of expensive low abundance reagents, but it drastically reduces the time needed to measure individual conditions in large volume cuvettes.
Topics: Acridine Orange; Vacuolar Proton-Translocating ATPases; Vacuoles; Endosomes; Saccharomyces cerevisiae; Lysosomes; Hydrogen-Ion Concentration
PubMed: 36167157
DOI: 10.1016/j.ab.2022.114927 -
Molecules (Basel, Switzerland) Mar 2020Frequent fungal infections in immunocompromised patients and mortality due to invasive mycosis are important clinical problems. Opportunistic pathogenic species remain... (Review)
Review
Frequent fungal infections in immunocompromised patients and mortality due to invasive mycosis are important clinical problems. Opportunistic pathogenic species remain one of the leading causes of systemic mycosis worldwide. The repertoire of antifungal chemotherapeutic agents is very limited. Although new antifungal drugs such as lanosterol 14α-demethylase and β-glucan synthase inhibitors have been introduced into clinical practice, the development of multidrug resistance has become increasingly significant. The urgency to expand the range of therapeutic options for the treatment of fungal infections has led researchers in recent decades to seek alternative antifungal targets to the conventional ones currently used. Among them, many compounds containing an acridine scaffold have been synthesized and tested. In this review, the applicability of acridines and their functional analogues acridones as antifungal agents is described. Acridine derivatives usage in photoantifungal chemotherapy, interactions with fungal transporters resulting in modulation of efflux/influx pumps and the effect of acridine derivatives on fungal topoisomerases are discussed. This article explores new perspectives on the mechanisms of antifungal acridine-peptide conjugates and acridine-based hybrid molecules to effectively combat fungal infections.
Topics: Acridines; Animals; Antifungal Agents; Biofilms; Drug Resistance, Fungal; Humans; Microbial Sensitivity Tests; Photosensitizing Agents
PubMed: 32218216
DOI: 10.3390/molecules25071480 -
BioMed Research International 2019Musculoskeletal sarcomas are rare and aggressive human malignancies affecting bones and soft tissues with severe consequences, in terms of both morbidity and mortality....
Musculoskeletal sarcomas are rare and aggressive human malignancies affecting bones and soft tissues with severe consequences, in terms of both morbidity and mortality. An innovative technique that combines photodynamic surgery (PDS) and therapy (PDT) with acridine orange has been recently suggested, showing promising results. However, due to the low incidence of sarcoma in humans, this procedure has been attempted only in pilot studies and stronger evidence is needed. Naturally occurring tumors in cats are well-established and advantageous models for human cancers. Feline injection-site sarcoma (FISS) shares with human musculoskeletal sarcomas a mesenchymal origin and an aggressive behavior with a high relapse rate. Furthermore, wide surgical excision is not always possible due to the size and site of development. We assessed the feasibility and the effectiveness of PDS and PDT with acridine orange to prevent FISS recurrence by treating a short case series of cats. For PDS, the surgical field was irrigated with an acridine orange solution and exposed to UV light to enlighten the residual tumor tissue, and the resultant fluorescent areas were trimmed. For PDT, before wound closure, the field was again irrigated with acridine orange solution and exposed to visible light to get the antitumoral cytocidal effect. The procedure was easy to perform and well tolerated, we did not observe any major complications, and all the surgical resection margins were free of disease. Finally, at follow-up, all treated patients did not show evidence of tumor recurrence and had a significantly higher event-free survival rate in respect to a control group treated only by surgery. In conclusion, by this study we demonstrated that, in FISS, PDS and PDT with acridine orange may improve local tumor control, granting a better outcome, and we laid the foundation to validate its effectiveness for the treatment of human musculoskeletal sarcomas.
Topics: Acridine Orange; Animals; Cats; Female; Humans; Male; Muscle Neoplasms; Photochemotherapy; Sarcoma
PubMed: 31360726
DOI: 10.1155/2019/8275935