Anticancer Potential of Mefenamic Acid Derivatives with Platelet-Derived Growth Factor Inhibitory Property
| Autor: | Snehal S. Patel, Jignasa K. Savjani, Vishal Chavda, Richa Tripathi |
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| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular Cancer Research Platelet-derived growth factor Angiogenesis Cell Survival medicine.medical_treatment Antineoplastic Agents Metastasis 03 medical and health sciences chemistry.chemical_compound Mefenamic Acid Structure-Activity Relationship 0302 clinical medicine Carcinoembryonic antigen In vivo medicine Tumor Cells Cultured Humans 030304 developmental biology Cell Proliferation Pharmacology Platelet-Derived Growth Factor 0303 health sciences biology Dose-Response Relationship Drug Molecular Structure Growth factor Hep G2 Cells medicine.disease Vascular endothelial growth factor chemistry 030220 oncology & carcinogenesis biology.protein Cancer research Molecular Medicine Drug Screening Assays Antitumor Platelet-derived growth factor receptor |
| Zdroj: | Anti-cancer agents in medicinal chemistry. 20(8) |
| ISSN: | 1875-5992 |
| Popis: | Background: Numerous studies suggest that non-steroidal anti-inflammatory drugs reduce cancer cell proliferation, progression, angiogenesis, apoptosis, and invasiveness. Objective: The current study focuses on the evaluation of novel mefenamic acid derivatives for the treatment of hepatocellular carcinoma. Methods: Derivatives were subjected to molecular modeling for prediction of pharmacological activity using software, followed by synthesis and in vitro assay. In in vivo study, disease was induced with N-Nitrosodiethylamine followed by 2-acetylaminofluorene orally for 2 weeks. After 12 weeks of induction, treatment was given for a period of one week. At the end of the treatment, determination of liver weight, a number of nodules, biochemical parameters, immunohistochemistry, histopathology, and gene expression studies, were carried out. Results: Based on molecular docking score for PDGF-α (Platelet-Derived Growth Factor) and IC50 values in HepG2 cell line study, JS-PFA was selected for the in vivo study where JS-PFA showed a statistically significant reduction in a number of nodules and liver weight. Protective role of JS-PFA has been observed in tumorspecific markers like α-fetoprotein, carcinoembryonic antigen, and lactate dehydrogenase levels. The JS-PFA has shown a significant reduction in PDGF-α levels as well as liver markers and total bilirubin levels. Histopathological analysis also showed a protective effect. The results of immunohistochemical analysis of P53 and down-regulation of vascular endothelial growth factor and matrix metalloproteinases-9 genes suggest that derivative inhibits PDGF mediated tumor growth and leads to apoptosis, inhibition of angiogenesis, and metastasis. Conclusion: The effectiveness of JS-PFA in our studies suggests targeting PDGF by COX 2 inhibitor can serve as a novel treatment strategy for the treatment of HCC. |
| Databáze: | OpenAIRE |
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