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

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.

• Authors: Snehal S Patel, Richa Tripathi, Vishal K Chavda, Jignasa K Savjani
• Journal: Anti-cancer agents in medicinal chemistry (Anticancer Agents Med Chem) Vol. 20 Issue 8 Pg. 998-1008 ( 2020) ISSN: 1875-5992 [Electronic] Netherlands
• PMID: 32294047 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright© Bentham Science Publishers; For any queries, please email at [email protected].

Chemical References

• Antineoplastic Agents
• Platelet-Derived Growth Factor
• platelet-derived growth factor A
• Mefenamic Acid

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Hep G2 Cells
• Humans
• Mefenamic Acid (chemical synthesis, chemistry, pharmacology)
• Models, Molecular
• Molecular Structure
• Platelet-Derived Growth Factor (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship
• Tumor Cells, Cultured