Back to Search Start Over

Conjugation of Diclofenac with Novel Oleanolic Acid Derivatives Modulate Nrf2 and NF-κB Activity in Hepatic Cancer Cells and Normal Hepatocytes Leading to Enhancement of Its Therapeutic and Chemopreventive Potential

Authors :
Maria Narożna
Violetta Krajka-Kuźniak
Barbara Bednarczyk-Cwynar
Małgorzata Kucińska
Robert Kleszcz
Jacek Kujawski
Hanna Piotrowska-Kempisty
Adam Plewiński
Marek Murias
Wanda Baer-Dubowska
Source :
Pharmaceuticals, Vol 14, Iss 7, p 688 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

Combining NSAIDs with conventional therapeutics was recently explored as a new strategy in cancer therapy. Our earlier studies showed that novel oleanolic acid oximes (OAO) conjugated with aspirin or indomethacin may enhance their anti-cancer potential through modulation of the Nrf2 and NF-κB signaling pathways. This study focused on the synthesis and biological evaluation of four diclofenac (DCL)–OAO derivative conjugates in the context of these pathways’ modification and hepatic cells survival. Treatment with the conjugates 4d, 3-diclofenacoxyiminoolean-12-en-28-oic acid morpholide, and 4c, 3-diclofenacoxyiminoolean-12-en-28-oic acid benzyl ester significantly reduced cell viability in comparison to the DCL alone. In THLE-2, immortalized normal hepatocytes treated with these conjugates resulted in the activation of Nrf2 and increased expression in SOD-1 and NQO1, while the opposite effect was observed in the HepG2 hepatoma cells. In both cell lines, reduced activation of the NF-κB and COX-2 expression was observed. In HepG2 cells, conjugates increased ROS production resulting from a reduced antioxidant defense, induced apoptosis, and inhibited cell proliferation. In addition, the OAO morpholide derivative and its DCL hybrid reduced the tumor volume in mice bearing xenografts. In conclusion, our study demonstrated that conjugating diclofenac with the OAO morpholide and a benzyl ester might enhance its anti-cancer activity in HCC.

Details

Language :
English
ISSN :
14248247
Volume :
14
Issue :
7
Database :
Directory of Open Access Journals
Journal :
Pharmaceuticals
Publication Type :
Academic Journal
Accession number :
edsdoj.39cc15d5559647a6ac4e1d3132e51342
Document Type :
article
Full Text :
https://doi.org/10.3390/ph14070688