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Discovery Medicine Jun 2023Amonafide (Amo), due to hematotoxicity and digestive tract symptoms, the clinical application of which is limited. Several studies have reported that chemotherapy side...
BACKGROUND
Amonafide (Amo), due to hematotoxicity and digestive tract symptoms, the clinical application of which is limited. Several studies have reported that chemotherapy side effects are closely related to cellular senescence accumulation. Our study aims to examine whether amonafide causes senescence in human umbilical vein endothelial cell (HUVEC) lines and investigate its mechanisms associated with senescence.
METHODS
The experiments of expression of genes and proteins associated with aging were carried out with HUVEC cell lines. The experiments were divided into a control group and an amonafide group with different days. The HUVEC senescence cells were detected by SA-β-Gal staining, Western blotting detected the protein levels of p16, p53, AMPK (Adenosine 5'-Monophosphate (AMP)-Activated Protein Kinase), mTOR (mechanistic Target of Rapamycin), p62, and LC3 (microtubule-associated protein1 light chain 3, MAP1LC3). Fluorescence detected the expression of mRFP (monomeric Red Fluorescent Protein)-GFP (Green Fluorescent Protein)-LC3 and LC3 puncta of HUVEC cells. RT-qPCR (Real-Time Quantitative Polymerase Chain Reaction) tested the expressions of , , (Interleukin), (Interleukin-6), (Interleukin-8), and (Monocyte Chemoattractant Protein-1). CCK-8 (Cell Counting Kit-8) assessed the HUVEC cell viability.
RESULTS
Here, we reported that amonafide resulted in an increased proportion of SA-β-Gal positive cells, high expression of aging-related proteins (p53 < 0.05; p16 < 0.05), and aging-related genes ( < 0.05; < 0.05; < 0.05; < 0.05; < 0.05; < 0.05) on the 3rd day. Mechanistically, amonafide could cause an increase in the levels of the mTOR ( < 0.05) on days 1 and 3, and p62 protein ( < 0.05) on day 1, and a decline in LC3II (microtubule-associated protein1 light chain 3Ⅱ)/LC3I levels ( < 0.05) on day 3, which is associated with the regulation of senescence. Additionally, the viability of HUVECs (human umbilical vein endothelial cells) was significantly inhibited by amonafide starting with a concentration of 0.8 μm ( < 0.05).
CONCLUSIONS
We first discovered that amonafide caused normal cellular senescence in our experiments. Amonafide-induced cellular aging by inhibiting autophagy and activating the mTOR pathway. The findings may offer new strategies for managing adverse reactions to amonafide.
Topics: Humans; Human Umbilical Vein Endothelial Cells; Interleukin-8; Tumor Suppressor Protein p53; Interleukin-6; TOR Serine-Threonine Kinases; Autophagy; Cellular Senescence
PubMed: 37272093
DOI: 10.24976/Discov.Med.202335176.27 -
Bioorganic Chemistry Dec 2019Novel water-soluble 4-aminonaphthalimides were synthesised and their cellular fluorescent imaging, cytotoxicity and ability to induced apoptosis evaluated. The lead...
Novel water-soluble 4-aminonaphthalimides were synthesised and their cellular fluorescent imaging, cytotoxicity and ability to induced apoptosis evaluated. The lead compound 1 was designed from the cross-fertilisation of the basic hydrophilic amino pharmacophore of mitoxantrone, and an aminonaphthalimide scaffold of the drug candidate, amonafide. The compounds are also fluorescent pH probes based on photoinduced electron transfer (PET) and internal charge transfer (ICT). The compounds are sensitive to solvent polarity with large Stoke shifts (>90 nm) and provide emissive-coloured solutions (blue to yellow). Excited state pKs of 9.0-9.3 and fluorescence quantum yields of 0.47-0.58 were determined in water. The cytotoxicity and cellular fluorescent imaging properties of the compounds were tested on human cancer cell lines K562 and MCF-7 by the MTT assay, phase contrast and fluorescence microscopy. Compounds 1 and 3 with flexible aminoalkyl chains exhibited GI comparable to amonafide, while 2 and 4 with a rigid piperazine moiety and butyl chain are less cytotoxic. Fluorescence microscopy with 1 allowed for the visualization of the intracellular microenvironment exemplifying the potential utility of such hybrid molecules as anticancer and fluorescent cellular imaging agents.
Topics: Adenine; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Fluorescent Dyes; Humans; Microscopy, Fluorescence; Mitoxantrone; Naphthalimides; Organophosphonates; Phthalimides; Spectrometry, Fluorescence
PubMed: 31561011
DOI: 10.1016/j.bioorg.2019.103287 -
Cancer Management and Research 2019Human melanoma is a malignant tumor originated from melanocytes with high invasion, metastasis, and poor prognosis. In this study, the effects of naphthalimides UNBS5162...
BACKGROUND
Human melanoma is a malignant tumor originated from melanocytes with high invasion, metastasis, and poor prognosis. In this study, the effects of naphthalimides UNBS5162 and amonafide on the properties of proliferation and apoptosis in human melanoma cells were confirmed.
METHODS
Cell proliferation was determined by CCK8 and clone formation assay. Transwell assay was performed to detect the migration and invasion of M14 and A375 cells. Cell apoptosis was estimated using flow cytometry.
RESULTS
In a drug sensitivity assay, cell viability decreased with increasing concentrations of UNBS5162 or amonafide. Likewise, proliferation of M14 or A375 cells treated with 10 μM UNBS5162 or 8 μM amonafide decreased significantly when compared with negative control (NC) cells, their inhibition effect verified by means of a clone formation assay. After the treatment with UNBS5162 or amonafide, the migration of melanoma cells was inhibited in a dosede-pendent manner. The number of invaded cells treated with UNBS5162 was also significantly reduced when compared with those of the NC cells. The apoptotic cell numbers treated with UNBS5162 or amonafide decreased significantly when compared with the M14 and A375 cells in the NC group. According to Western blot results, phosphorylation of AKT and expressions of mesenchymal marker factors were inhibited in cells treated with UNBS5162 or amonafide.
CONCLUSION
These results reveal that UNBS5162 inhibits the cell activity of melanoma cells through the AKT/mTOR signaling pathway, and reverses epithelial-mesenchymal transition conversion in human melanoma cells. This study on UNBS5162 and amonafide in melanomas provides an experimental basis of their uses and potential value on human melanoma treatment.
PubMed: 30962721
DOI: 10.2147/CMAR.S177623 -
Frontiers in Endocrinology 2023Gliomas are the most common intracranial nervous system tumours that are highly malignant and aggressive, and mitochondria are an important marker of metabolic...
BACKGROUND
Gliomas are the most common intracranial nervous system tumours that are highly malignant and aggressive, and mitochondria are an important marker of metabolic reprogramming of tumour cells, the prognosis of which cannot be accurately predicted by current histopathology. Therefore, Identify a mitochondrial gene with immune-related features that could be used to predict the prognosis of glioma patients.
METHODS
Gliomas data were downloaded from the TCGA database and mitochondrial-associated genes were obtained from the MITOCARTA 3.0 dataset. The CGGA, kamoun and gravendeel databases were used as external datasets. LASSO(Least absolute shrinkage and selection operator) regression was applied to identify prognostic features, and area and nomograms under the ROC(Receiver Operating Characteristic) curve were used to assess the robustness of the model. Single sample genomic enrichment analysis (ssGSEA) was employed to explore the relationship between model genes and immune infiltration, and drug sensitivity was used to identify targeting drugs. Cellular studies were then performed to demonstrate drug killing against tumours.
RESULTS
COX assembly mitochondrial protein homolog (), Cytochrome c oxidase protein 20 homolog () and Cytochrome b-c1 complex subunit 7 () were identified as prognostic key genes in glioma, with , progressively increasing and progressively decreasing with decreasing risk scores. ROC curve analysis of the TCGA training set model yielded AUC (Area Under The Curve) values >0.8 for 1-, 2- and 3-year survival, and the model was associated with both CD8+ T cells and immune checkpoints. Finally, using cellMiner database and molecular docking, it was confirmed that binds covalently to Amonafide lysine at position 78 and threonine at position 82, while cellular assays showed that Amonafide inhibits glioma migration and invasion.
CONCLUSION
Our three mitochondrial genomic composition-related features accurately predict Survival in glioma patients, and we also provide glioma chemotherapeutic agents that may be mitochondria-related targets.
Topics: Humans; Prognosis; Molecular Docking Simulation; Precision Medicine; DNA, Mitochondrial; Glioma; Mitochondria
PubMed: 37091853
DOI: 10.3389/fendo.2023.1172182 -
Expert Opinion on Drug Metabolism &... Jan 2021The N-acetylation polymorphism has been the subject of comprehensive reviews describing the role of arylamine N-acetyltransferase 2 (NAT2) in the metabolism of numerous... (Review)
Review
INTRODUCTION
The N-acetylation polymorphism has been the subject of comprehensive reviews describing the role of arylamine N-acetyltransferase 2 (NAT2) in the metabolism of numerous aromatic amine and hydrazine drugs.
AREAS COVERED
We describe and review data that more clearly defines the effects of haplotypes and genotypes on the expression of acetylator phenotype towards selected drugs within human hepatocytes in vitro, within human hepatocyte cultures in situ, and clinical measures such as bioavailability, plasma metabolic ratios of parent to N-acetyl metabolite, elimination rate constants and plasma half-life, and/or clearance determinations in human subjects. We review several drugs (isoniazid, hydralazine, sulfamethazine, amifampridine, procainamide, sulfasalazine, amonafide and metamizole) for which phenotype-guided therapy may be important. The value of pharmacogenomics-guided isoniazid therapy for the prevention and treatment of tuberculosis is presented as a paradigm for phenotype-dependent dosing strategies.
EXPERT OPINION
Studies in human subjects and cryopreserved human hepatocytes show evidence for rapid, intermediate and slow acetylator phenotypes, with further data suggesting genetic heterogeneity within the slow acetylator phenotype. Incorporation of more robust genotype/phenotypes relationships, including genetic heterogeneity within the slow acetylator phenotype, should lead to further advancements in both health outcomes and cost benefit for prevention and treatment of tuberculosis.
Topics: Acetylation; Amines; Arylamine N-Acetyltransferase; Genotype; Hepatocytes; Humans; Hydrazines; Pharmaceutical Preparations; Pharmacogenetics; Polymorphism, Single Nucleotide
PubMed: 33094670
DOI: 10.1080/17425255.2021.1840551 -
Bioorganic Chemistry Apr 20221,8-Naphthalimide moiety is well known to possess various biological activities as it can very well intercalate with DNA. In recent years, much of the attention has been... (Review)
Review
1,8-Naphthalimide moiety is well known to possess various biological activities as it can very well intercalate with DNA. In recent years, much of the attention has been given to the preparation of naphthalimide derivatives by substitution at various positions of the 1,8-naphthalimide ring for their exploration as anticancer agents. These derivatives possess different anticancer properties, which cover a broader range of cancer cell lines. Interestingly, some derivatives include enhanced activity than the reference standards like cisplatin, amonafide, mitonafide, etc., and be selective against the cell lines. The aim is to study the effect of different modulations at various positions of the 1,8-naphthalimide ring with a polyamine, thiourea, benzothiazole, benzimidazole, and formation of metal complexes and bis-naphthalimides that affects the overall cytotoxic properties of the resulting 1,8-naphthalimides. Moreover, the structure-activity relationship of these variations for the resulting derivatives' anticancer properties has also been discussed. Thus, this review will be important for a wide range of researchers to design and development of various 1,8-naphthalimide derivatives with desired drug profiles.
Topics: Antineoplastic Agents; Cell Line, Tumor; DNA; Humans; Naphthalimides; Neoplasms; Structure-Activity Relationship
PubMed: 35202852
DOI: 10.1016/j.bioorg.2022.105677 -
Bioorganic & Medicinal Chemistry Letters Apr 2023A series of mono- and bisnaphthalimides derivatives containing 3-nitro and 4-morpholine moieties were designed, synthesized, and evaluated for their in vitro anticancer...
A series of mono- and bisnaphthalimides derivatives containing 3-nitro and 4-morpholine moieties were designed, synthesized, and evaluated for their in vitro anticancer activities against four cancer cell lines. Some compounds exhibited relatively good antiproliferative activity on the cell lines tested, in comparison with mitonafide and amonafide. It is noteworthy that bisnaphthalimide A6 was identified as the most potent compound in anti-proliferation against MGC-803 cells, with an IC lowered to 0.09 μM, a far greater potency than that of mono-naphthalimide A7, mitonafide, and amonafide. A gel electrophoresis assay revealed that DNA and Topo I were the potential targets of compounds A6 and A7. The treatment of CNE-2 cells with compounds A6 and A7 resulted in an S phase cell cycle arrest, accompanied by the upregulation of the expression levels of the antioncogene p27 and the down-regulation of the expression levels of CDK2 and cyclin E. In addition, compounds A6 and A7-induced apoptosis was further confirmed by flow cytometry, ROS generation assay, and Hoechst 33,258 staining. In particular, in vivo antitumor assay results revealed that bisnaphthalimide A6 exhibited potent anticancer efficiency in an MGC-803 xenograft tumor model, in comparison with mitonafide, and had lower toxicity than mono-naphthalimide A7. In brief, the results suggested that bisnaphthalimide derivatives containing 3-nitro and 4-morpholine moieties might serve as DNA binding agents for the development of new antitumor agents.
Topics: Humans; Drug Screening Assays, Antitumor; Antineoplastic Agents; Apoptosis; DNA; Morpholines; Cell Line, Tumor; Cell Proliferation; Structure-Activity Relationship; Molecular Structure
PubMed: 36894107
DOI: 10.1016/j.bmcl.2023.129218 -
Chemical Biology & Drug Design May 2017With the aim of upregulating antitumor efficacy and downregulating adverse effects, the amino group in the three-position of amonafide aromatic ring was modified by...
With the aim of upregulating antitumor efficacy and downregulating adverse effects, the amino group in the three-position of amonafide aromatic ring was modified by coupling with different amine/polyamine motifs via two linkers. Two series of naphthalimide derivatives were designed and synthesized and evaluated for their antitumor properties in vitro and in vivo. The preliminary in vitro trials revealed that compounds with urea as the linker were not active, and the presence of aspirin elevated the potency of 6k against tumor cells, wound healing, and the protein expression of cyclic D1 and MMP9. The in vivo trials on three H22 tumor transplant models demonstrated that the combination of 6k and aspirin markedly improved the efficacy in terms of inhibitive effect, pulmonary metastasis, and extension of the life span. More importantly, the combination of 6k and aspirin displayed the reduced side-effects compared to that of amonafide.
Topics: Adenine; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Microscopy, Fluorescence; Naphthalimides; Neoplasms; Organophosphonates; Polyamines; Transplantation, Heterologous
PubMed: 27762101
DOI: 10.1111/cbdd.12888 -
Bioorganic & Medicinal Chemistry Jul 2015A novel series of 5-arylcarbamoyl- and 5-arylmethyl-2-methylisoxazolidin-3-yl-3-phosphonates have been synthesized via cycloaddition of...
A novel series of 5-arylcarbamoyl- and 5-arylmethyl-2-methylisoxazolidin-3-yl-3-phosphonates have been synthesized via cycloaddition of N-methyl-C-(diethoxyphosphoryl)nitrone with N-substituted naphthalimide acrylamides and N-allylnaphthalimides. All cis- and trans-isoxazolidine phosphonates obtained herein were assessed for antiviral activity against a broad range of DNA and RNA viruses. Isoxazolidines trans-9d and trans-9f exhibited the highest activity (EC50=8.9μM) toward cytomegalovirus. Compounds cis- and trans-9d as well as cis- and trans-9f were found potent against HSV and Vaccinia viruses (EC50 in the 45-58μM range), whereas isoxazolidines 10a and 10d suppressed replication of Coxsackie B4 and Punta Toro viruses (EC50 in the 45-73μM range). Antiproliferative evaluation of all obtained isoxazolidines revealed the promising activity of cis-9b, cis-9d, trans-9d, cis-9e, trans-9e, cis-9f and trans-9f toward tested cancer cell lines with IC50 in the 1.1-19μM range.
Topics: Acrylamides; Adenine; Antineoplastic Agents; Antiviral Agents; Cell Line, Tumor; Cell Survival; Cycloaddition Reaction; Cytomegalovirus; Cytostatic Agents; Drug Design; Enterovirus; Humans; Isoxazoles; Naphthalimides; Nitrogen Oxides; Organophosphonates; Phlebovirus; Simplexvirus; Structure-Activity Relationship; Vaccinia virus
PubMed: 26001344
DOI: 10.1016/j.bmc.2015.04.079 -
European Journal of Medicinal Chemistry Jan 2021Four series of new 3-nitro naphthalimides derivatives, 4(4a‒4f), 5(5a‒5i), 6(6a‒6e) and 7 (7a‒7j), were designed and synthesized as antitumor agents. Methyl...
Four series of new 3-nitro naphthalimides derivatives, 4(4a‒4f), 5(5a‒5i), 6(6a‒6e) and 7 (7a‒7j), were designed and synthesized as antitumor agents. Methyl thiazolyl tetrazolium (MTT) screening assay results revealed that some compounds displayed effective in vitro antiproliferative activity on SMMC-7721, T24, SKOV-3, A549 and MGC-803 cancer cell lines in comparison with 5-fluorouracil (5-FU), mitonafide and amonafide. Nude mouse xenotransplantation model assay results indicated that compounds 6b and 7b exhibited good in vivo antiproliferative activity in MGC-803 xenografts in comparison with amonafide and cisplatin, suggesting that compounds 6b and 7b could be good candidates for antitumor agents. Gel electrophoresis assay indicated that DNA and Topo I were the potential targets of compounds 6b and 7b, and comet assay confirmed that compounds 6b and 7b could induce DNA damage, while the further study showed that the 6b- and 7b-induced DNA damage was accompanied by the upregulation of p-ATM, P-Chk2, Cdc25A and p-H2AX. Cell cycle arrest studies demonstrated that compounds 6b and 7b arrested the cell cycle at the S phase, accompanied by the upregulation of the expression levels of the antioncogene p21 and the down-regulation of the expression levels of cyclin E. Apoptosis assays indicated that compounds 6b and 7b caused the apoptosis of tumor cells along with the upregulation of the expression of Bax, caspase-3, caspase-9 and PARP and the downregulation of Bcl-2. These mechanistic studies suggested that compounds 6b and 7b exerted their antitumor activity by targeting to DNA, thereby inducing DNA damage and Topo I inhibition, and consequently causing S stage arrest and the induction of apoptosis.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; DNA Damage; Drug Design; Humans; Mice, Nude; Naphthalimides; Neoplasms; Mice
PubMed: 33109400
DOI: 10.1016/j.ejmech.2020.112951