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Cancers Nov 2023: Drug repurposing is a strategy that complements the conventional approach of developing new drugs. Hepatocellular carcinoma (HCC) is a highly prevalent type of liver...
: Drug repurposing is a strategy that complements the conventional approach of developing new drugs. Hepatocellular carcinoma (HCC) is a highly prevalent type of liver cancer, necessitating an in-depth understanding of the underlying molecular alterations for improved treatment. : We searched for a vast array of microarray experiments in addition to RNA-seq data. Through rigorous filtering processes, we have identified highly representative differentially expressed genes (DEGs) between tumor and non-tumor liver tissues and identified a distinct class of possible new candidate drugs. : Functional enrichment analysis revealed distinct biological processes associated with metal ions, including zinc, cadmium, and copper, potentially implicating chronic metal ion exposure in tumorigenesis. Conversely, up-regulated genes are associated with mitotic events and kinase activities, aligning with the relevance of kinases in HCC. To unravel the regulatory networks governing these DEGs, we employed topological analysis methods, identifying 25 hub genes and their regulatory transcription factors. In the pursuit of potential therapeutic options, we explored drug repurposing strategies based on computational approaches, analyzing their potential to reverse the expression patterns of key genes, including AURKA, CCNB1, CDK1, RRM2, and TOP2A. Potential therapeutic chemicals are alvocidib, AT-7519, kenpaullone, PHA-793887, JNJ-7706621, danusertibe, doxorubicin and analogues, mitoxantrone, podofilox, teniposide, and amonafide. : This multi-omic study offers a comprehensive view of DEGs in HCC, shedding light on potential therapeutic targets and drug repurposing opportunities.
PubMed: 38067357
DOI: 10.3390/cancers15235653 -
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 -
Food Safety (Tokyo, Japan) Dec 2022Cytochrome P450 (CYP)-mediated metabolisms of four chemicals have been investigated to understand their unresolved phenomena of their metabolisms using human...
Cytochrome P450 (CYP)-mediated metabolisms of four chemicals have been investigated to understand their unresolved phenomena of their metabolisms using human CYP-Template systems developed in our previous studies (Drug Metab Pharmacokinet 2019, 2021, 2022). Simulation experiments of a topoisomerase-targeting agent, amonafide, offered a possible new inhibitory-mechanism as Trigger-residue inactivation on human CYP1A2 Template. -Acetylamonafide as well as amonafide would inactivate CYP1A2 through the interference of Trigger-residue movement with their dimethylaminoethyl parts. The mechanism was also supported on the inhibition/inactivation of two other drugs, DSP-1053 and binimetinib. Both the drugs, after other CYP-mediated slight structural alterations, were expected to interact with Trigger-residue for the intense inhibition on CYP1A2 Template. Possible formation of reactive intermediates of amonafide and 3-methylindole was also examined on CYP1A2 Template. Placements of amonafide suggested the scare -oxidation of the arylamine part due to the Trigger-residue interaction. Placements of 3-methylindole suggested the formation of a reactive intermediate, 3-methyleneindolenine, rather selectively on rodent CYP1A2 than on human CYP1A2, in consistent with the experimental data. These results suggest that CYP Template systems developed are effective tools to warn an appearance of unstable reactive intermediates. Our CYP-Template systems would support confident judgements in safety assessments through offering the mechanistic understandings of the metabolism.
PubMed: 36619007
DOI: 10.14252/foodsafetyfscj.D-22-00008 -
The Tohoku Journal of Experimental... Aug 2022The current work screened differentially expressed genes (DEGs) related to advanced clear cell renal cell carcinoma (ccRCC) and found potential biomarkers and drugs for...
The current work screened differentially expressed genes (DEGs) related to advanced clear cell renal cell carcinoma (ccRCC) and found potential biomarkers and drugs for advanced ccRCC. After analyzing GSE53757 and GSE66271, we identified DEGs and performed the functional annotation, pathway enrichment, validation, survival analysis, and candidate drug analysis. We obtained 861 common DEGs from datasets between advanced ccRCC tissues and normal kidney tissues. Besides, we performed functional analysis under ontological conditions and carried out pathway analysis. The five most stable core gene groups and top 10 genes were screened using the Cytoscape software. We performed functional and pathway analyses again and found that the core genes were similar to total DEGs. After verification, the expression trends of the 10 hub genes did not change. Survival analysis showed high expressions of TOP2A, BIRC5, BUB1, MELK, RRM2, and TPX2 genes, suggesting that they might participate in cancer occurrence, migration, and relapse of ccRCC. The gene-drug analysis showed that gallium nitrate, cladribine, and amonafide were strongly associated with RRM2 and TOP2A. We found that RRM2 and TOP2A might be predictive biomarkers and novel targeted therapy for advanced ccRCC. These drugs (gallium nitrate, cladribine, and amonafide) might be used for treating advanced ccRCC.
Topics: Biomarkers, Tumor; Carcinoma, Renal Cell; Cladribine; Computational Biology; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms; Neoplasm Recurrence, Local; Prognosis; Protein Serine-Threonine Kinases
PubMed: 35896362
DOI: 10.1620/tjem.2022.J059 -
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 -
Frontiers in Chemistry 2020Naphthalimides, such as amonafide and mitonafide in clinical trials, have been developed as antitumor agents for orthotopic tumor. However, the serious side effects in...
Naphthalimides, such as amonafide and mitonafide in clinical trials, have been developed as antitumor agents for orthotopic tumor. However, the serious side effects in cancer patients limit their applications. Herein, a new class of polyamine-based naphthalimide conjugates , , and with and without the alkylation of the distant nitrogen in the polyamine chain were synthesized and the mechanism was determined. Compared with amonafide, dinitro-naphthalimide conjugate with a 4,3-cyclopropyl motif preferentially accumulates in cancer cells and minimizes side effects and . More importantly, at the dosage of as low as 3 mg/kg (57.97%) displays better antitumor effects than the positive control amonafide (53.27%) at 5 mg/kg . And a remarkably elevated antitumor activity and a reduced toxicity are also observed for at 5 mg/kg (65.90%). The upregulated p53 and the apoptotic cells (73.50%) indicate that the mechanism of to induce apoptosis may result from its enhanced DNA damage. Further investigation indicates that in addition to target DNA, can modulate the polyamine homeostasis by upregulating polyamine oxidase (PAO) in a different way from that of amonafide. And also by targeting PTs overexpressed in most of cancer cells, downregulates the contents of Put, Spd, and Spm, which are in favor of suppressing fast-growing tumor cells. Our study implies a promising strategy for naphthalimide conjugates to treat hepatic carcinoma with notable activities and reduced toxicities at a low dosage.
PubMed: 32328475
DOI: 10.3389/fchem.2020.00166 -
Cancers Feb 2020Colorectal cancer (CRC) is one of the most prevalent cancers due to its frequency and high rate of mortality. Polyamine-vectorized anticancer drugs possess multiple...
Colorectal cancer (CRC) is one of the most prevalent cancers due to its frequency and high rate of mortality. Polyamine-vectorized anticancer drugs possess multiple biological properties. Of these drugs, 9F has been shown to inhibit tumor growth and the metastasis of hepatocellular carcinoma. This current study aims to investigate the effects of 9F on CRC and determine its molecular mechanisms of action. Our findings demonstrate that 9F inhibits CRC cell growth by inducing apoptosis and cell cycle arrest, and suppresses migration, invasion and angiogenesis in vitro, resulting in the inhibition of tumor growth and metastasis in vivo. Based on RNA-seq data, further bioinformatic analyses suggest that 9F exerts its anticancer activities through p53 signaling, which is responsible for the altered expression of key regulators of the cell cycle, apoptosis, the epithelial-to-mesenchymal transition (EMT), and angiogenesis. In addition, 9F is more effective than amonafide against CRC. These results show that 9F can be considered as a potential strategy for CRC treatment.
PubMed: 32106543
DOI: 10.3390/cancers12030528 -
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 -
MedChemComm Jan 2019A new series of different naphthalimide-benzothiazole/cinnamide derivatives were designed, synthesized and tested for their cytotoxicity on selected human cancer cell...
A new series of different naphthalimide-benzothiazole/cinnamide derivatives were designed, synthesized and tested for their cytotoxicity on selected human cancer cell lines. Among them, derivatives and with the 6-aminobenzothiazole ring and with the cinnamide ring displayed potent cytotoxic activity against colon (IC: 3.715 and 3.467 μM) and lung cancer (IC: 4.074 and 3.890 μM) cell lines when compared to amonafide (IC: 5.459 and 7.762 μM). Later, the DNA binding studies for these selected derivatives (by CD, UV/vis, fluorescence spectroscopy, DNA viscosity, and molecular docking) suggested that these new derivatives significantly intercalate between two strands of DNA. In addition, the most potent derivatives and were also found to inhibit DNA topoisomerase-II.
PubMed: 30774856
DOI: 10.1039/c8md00395e -
FASEB Journal : Official Publication of... Dec 2017Hepatocellular carcinoma (HCC) is the third leading form of cancer worldwide, and its incidence is increasing rapidly in the United States, tripling over the past 3...
Hepatocellular carcinoma (HCC) is the third leading form of cancer worldwide, and its incidence is increasing rapidly in the United States, tripling over the past 3 decades. The current chemotherapeutic strategies against localized and metastatic HCC are ineffective. Here we report that 6-methoxyethylamino-numonafide (MEAN) is a potent growth inhibitor of murine xenografts of 2 human HCC cell lines. At the same dose and with the same treatment strategies, MEAN was more efficacious in inhibiting tumor growth in mice than sorafenib, the only approved drug for HCC. Treatment by MEAN at an effective dose for 6 wk was well tolerated by animals. Combined therapy using both sorafenib and MEAN enhanced tumor growth inhibition over monotherapy with either agent. Additional experiments revealed that MEAN inhibited tumor growth through mechanisms distinct from those of either its parent compound, amonafide, or sorafenib. MEAN suppressed C-MYC expression and increased expression of several tumor suppressor genes, including Src homology region 2 domain-containing phosphatase-1 () and (thioredoxin-interacting protein). As an encouraging feature for envisioned clinical application, the IC of MEAN was not significantly changed in several drug-resistant cell lines with activated P-glycoprotein drug efflux pumps compared to drug-sensitive parent cells, demonstrating the ability of MEAN to be effective in cells resistant to existing chemotherapy regimens. MEAN is a promising candidate for clinical development as a single-agent therapy or in combination with sorafenib for the management of HCC.-Liu, Y., Lou, G., Norton, J. T., Wang, C., Kandela, I., Tang, S., Shank, N. I., Gupta, P., Huang, M., Avram, M. J., Green, R., Mazar, A., Appella, D., Chen, Z., Huang, S. 6-Methoxyethylamino-numonafide inhibits hepatocellular carcinoma xenograft growth as a single agent and in combination with sorafenib.
Topics: Alanine Transaminase; Animals; Antineoplastic Agents; Apoptosis; Aspartate Aminotransferases; Blotting, Western; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Female; Hep G2 Cells; Humans; Liver Neoplasms; Male; Mice; Naphthalimides; Niacinamide; Phenylurea Compounds; Sorafenib; Xenograft Model Antitumor Assays
PubMed: 28821631
DOI: 10.1096/fj.201700306RR