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The Effect of Novel Oleanolic Acid Oximes Conjugated with Indomethacin on the Nrf2-ARE And NF-κB Signaling Pathways in Normal Hepatocytes and Human Hepatocellular Cancer Cells
Nrf2 and NF-κB play a key role in inflammation-driven cancers. Conjugation of anti-inflammatory drugs with oleanolic acid oxime (OAO) may enhance their therapeutic potential as a result of downregulation of these pathways. Novel OAO derivatives conjugated with indomethacin (IND) were synthesized, an...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824409/ https://www.ncbi.nlm.nih.gov/pubmed/33396453 http://dx.doi.org/10.3390/ph14010032 |
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author | Narożna, Maria Krajka-Kuźniak, Violetta Bednarczyk-Cwynar, Barbara Kleszcz, Robert Baer-Dubowska, Wanda |
author_facet | Narożna, Maria Krajka-Kuźniak, Violetta Bednarczyk-Cwynar, Barbara Kleszcz, Robert Baer-Dubowska, Wanda |
author_sort | Narożna, Maria |
collection | PubMed |
description | Nrf2 and NF-κB play a key role in inflammation-driven cancers. Conjugation of anti-inflammatory drugs with oleanolic acid oxime (OAO) may enhance their therapeutic potential as a result of downregulation of these pathways. Novel OAO derivatives conjugated with indomethacin (IND) were synthesized, and their effect on the activation and expression of Nrf2 and NF-κB in HepG2 hepatoma cells and THLE-2 immortalized normal hepatocytes was evaluated in relation to cell cycle arrest and apoptosis. Treatment with OAO–IND conjugates reduced the activation of Nrf2 and NF-κB and the expression of their active forms in HepG2 cells, while in normal hepatocytes, the activation of Nrf2 was increased and NF-κB diminished. Compounds 3d, 3-indomethacinoxyiminoolean-12-en-28-oic acid morpholide, and 3c, 3-indomethacinoxyiminoolean-12-en-28-oic acid benzyl ester, were the most efficient. In THLE-2 cells, as opposed to HepG2 cells, the expressions of SOD-1 and NQO1 were significantly enhanced after treatment with these compounds. The COX-2 expression was diminished in both cell lines. OAO–IND derivatives affected the cell cycle arrest at G2/M, leading to increased apoptosis and increased number of resting HepG2 cells. Therefore, the conjugation of IND with OAO derivatives may preserve cancer cells against chemoresistance through the inhibition of the Nrf2-ARE pathway and NF-κB and, at the same time, exert a chemopreventive effect in normal hepatocytes. |
format | Online Article Text |
id | pubmed-7824409 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-78244092021-01-24 The Effect of Novel Oleanolic Acid Oximes Conjugated with Indomethacin on the Nrf2-ARE And NF-κB Signaling Pathways in Normal Hepatocytes and Human Hepatocellular Cancer Cells Narożna, Maria Krajka-Kuźniak, Violetta Bednarczyk-Cwynar, Barbara Kleszcz, Robert Baer-Dubowska, Wanda Pharmaceuticals (Basel) Article Nrf2 and NF-κB play a key role in inflammation-driven cancers. Conjugation of anti-inflammatory drugs with oleanolic acid oxime (OAO) may enhance their therapeutic potential as a result of downregulation of these pathways. Novel OAO derivatives conjugated with indomethacin (IND) were synthesized, and their effect on the activation and expression of Nrf2 and NF-κB in HepG2 hepatoma cells and THLE-2 immortalized normal hepatocytes was evaluated in relation to cell cycle arrest and apoptosis. Treatment with OAO–IND conjugates reduced the activation of Nrf2 and NF-κB and the expression of their active forms in HepG2 cells, while in normal hepatocytes, the activation of Nrf2 was increased and NF-κB diminished. Compounds 3d, 3-indomethacinoxyiminoolean-12-en-28-oic acid morpholide, and 3c, 3-indomethacinoxyiminoolean-12-en-28-oic acid benzyl ester, were the most efficient. In THLE-2 cells, as opposed to HepG2 cells, the expressions of SOD-1 and NQO1 were significantly enhanced after treatment with these compounds. The COX-2 expression was diminished in both cell lines. OAO–IND derivatives affected the cell cycle arrest at G2/M, leading to increased apoptosis and increased number of resting HepG2 cells. Therefore, the conjugation of IND with OAO derivatives may preserve cancer cells against chemoresistance through the inhibition of the Nrf2-ARE pathway and NF-κB and, at the same time, exert a chemopreventive effect in normal hepatocytes. MDPI 2020-12-31 /pmc/articles/PMC7824409/ /pubmed/33396453 http://dx.doi.org/10.3390/ph14010032 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Narożna, Maria Krajka-Kuźniak, Violetta Bednarczyk-Cwynar, Barbara Kleszcz, Robert Baer-Dubowska, Wanda The Effect of Novel Oleanolic Acid Oximes Conjugated with Indomethacin on the Nrf2-ARE And NF-κB Signaling Pathways in Normal Hepatocytes and Human Hepatocellular Cancer Cells |
title | The Effect of Novel Oleanolic Acid Oximes Conjugated with Indomethacin on the Nrf2-ARE And NF-κB Signaling Pathways in Normal Hepatocytes and Human Hepatocellular Cancer Cells |
title_full | The Effect of Novel Oleanolic Acid Oximes Conjugated with Indomethacin on the Nrf2-ARE And NF-κB Signaling Pathways in Normal Hepatocytes and Human Hepatocellular Cancer Cells |
title_fullStr | The Effect of Novel Oleanolic Acid Oximes Conjugated with Indomethacin on the Nrf2-ARE And NF-κB Signaling Pathways in Normal Hepatocytes and Human Hepatocellular Cancer Cells |
title_full_unstemmed | The Effect of Novel Oleanolic Acid Oximes Conjugated with Indomethacin on the Nrf2-ARE And NF-κB Signaling Pathways in Normal Hepatocytes and Human Hepatocellular Cancer Cells |
title_short | The Effect of Novel Oleanolic Acid Oximes Conjugated with Indomethacin on the Nrf2-ARE And NF-κB Signaling Pathways in Normal Hepatocytes and Human Hepatocellular Cancer Cells |
title_sort | effect of novel oleanolic acid oximes conjugated with indomethacin on the nrf2-are and nf-κb signaling pathways in normal hepatocytes and human hepatocellular cancer cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824409/ https://www.ncbi.nlm.nih.gov/pubmed/33396453 http://dx.doi.org/10.3390/ph14010032 |
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