Anticancer Potential of Mefenamic Acid Derivatives with Platelet-Derived Growth Factor Inhibitory Property

Author(s): Snehal S. Patel*, Richa Tripathi, Vishal K. Chavda, Jignasa K. Savjani

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 20 , Issue 8 , 2020


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Graphical Abstract:


Abstract:

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.

Keywords: Anticarcinogenic agents, cyclooxygenase 2, carcinoma, hepatocellular, mefenamic acid, platelet-derived growth factor.

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Article Details

VOLUME: 20
ISSUE: 8
Year: 2020
Published on: 24 July, 2020
Page: [998 - 1008]
Pages: 11
DOI: 10.2174/1871520620666200415100614
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