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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

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 signal...

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Autores principales: Narożna, Maria, Krajka-Kuźniak, Violetta, Bednarczyk-Cwynar, Barbara, Kucińska, Małgorzata, Kleszcz, Robert, Kujawski, Jacek, Piotrowska-Kempisty, Hanna, Plewiński, Adam, Murias, Marek, Baer-Dubowska, Wanda
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308582/
https://www.ncbi.nlm.nih.gov/pubmed/34358114
http://dx.doi.org/10.3390/ph14070688
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author Narożna, Maria
Krajka-Kuźniak, Violetta
Bednarczyk-Cwynar, Barbara
Kucińska, Małgorzata
Kleszcz, Robert
Kujawski, Jacek
Piotrowska-Kempisty, Hanna
Plewiński, Adam
Murias, Marek
Baer-Dubowska, Wanda
author_facet Narożna, Maria
Krajka-Kuźniak, Violetta
Bednarczyk-Cwynar, Barbara
Kucińska, Małgorzata
Kleszcz, Robert
Kujawski, Jacek
Piotrowska-Kempisty, Hanna
Plewiński, Adam
Murias, Marek
Baer-Dubowska, Wanda
author_sort Narożna, Maria
collection PubMed
description 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.
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spelling pubmed-83085822021-07-25 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 Narożna, Maria Krajka-Kuźniak, Violetta Bednarczyk-Cwynar, Barbara Kucińska, Małgorzata Kleszcz, Robert Kujawski, Jacek Piotrowska-Kempisty, Hanna Plewiński, Adam Murias, Marek Baer-Dubowska, Wanda Pharmaceuticals (Basel) Article 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. MDPI 2021-07-17 /pmc/articles/PMC8308582/ /pubmed/34358114 http://dx.doi.org/10.3390/ph14070688 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Narożna, Maria
Krajka-Kuźniak, Violetta
Bednarczyk-Cwynar, Barbara
Kucińska, Małgorzata
Kleszcz, Robert
Kujawski, Jacek
Piotrowska-Kempisty, Hanna
Plewiński, Adam
Murias, Marek
Baer-Dubowska, Wanda
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308582/
https://www.ncbi.nlm.nih.gov/pubmed/34358114
http://dx.doi.org/10.3390/ph14070688
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