Abstract
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.
Highlights
Occurring triterpenoids, including oleanolic acid (OA), 3-β-hydroxyolean-12en-28-oic acid, possess, besides other biological activities, an anti-inflammatory potential [1].Prolonged inflammation resulting from viral hepatitis and/or metabolic disorders [2] is estimated to be the major cause of hepatocellular carcinoma (HCC) growth
Conjugation with ASP enhanced Nrf2 activation in normal THLE-2 cells, while in HepG2 cells, this effect was less pronounced compared with that in nonconjugated oleanolic acid oxime (OAO). These results suggested that OAO themselves, OAO substituted with morpholide, may be deemed therapeutic agents, while OAO
Taking into consideration the differences in the mechanism of COX inhibition by these two nonsteroidal anti-inflammatory drugs (NSAIDs), the aim of this study was to appraise the effect of the new synthesized conjugates of previously investigated OAO derivatives with indomethacin on Nrf2 and NF-κB signaling in connection with cell cycle distribution, apoptosis, and proliferation in normal hepatocytes and HCC cell lines
Summary
Occurring triterpenoids, including oleanolic acid (OA), 3-β-hydroxyolean-12en-28-oic acid, possess, besides other biological activities, an anti-inflammatory potential [1].Prolonged inflammation resulting from viral hepatitis and/or metabolic disorders [2] is estimated to be the major cause of hepatocellular carcinoma (HCC) growth. Several studies have demonstrated that treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce the incidence and mortality of a wide range of tumors, including HCC [3,4]. Treatment with these drugs is often associated with adverse effects that mainly affect the gastrointestinal mucosa and cause liver dysfunction [5]. Oxidative stress has been implicated as a general mechanism in the toxicity of many. It was reported that NSAIDs produce reactive oxygen species (ROS) inside cells [7], resulting in oxidative stress [8,9]
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