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Indomethacin and Diclofenac Hybrids with Oleanolic Acid Oximes Modulate Key Signaling Pathways in Pancreatic Cancer
Maria Narożna1,2, Violetta Krajka-Kuźniak1, Robert Kleszcz1
1Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, 4, Święcicki Street, 60-781 Poznań, Poland.
Abstract:
Our earlier studies showed that coupling nonsteroidal anti-inflammatory drugs (NSAIDs) with oleanolic acid derivatives increased their anti-inflammatory activity in human hepatoma cells. The aim of this study was to evaluate their effect on the signaling pathways involved in inflammation processes in human pancreatic cancer (PC) cells. Cultured PSN-1 cells were exposed for 24 h (30 µM) to OA oxime (OAO) derivatives substituted with benzyl or morpholide groups and their conjugates with indomethacin (IND) or diclofenac (DCL). The activation of NF-κB and Nrf2 was assessed by the evaluation of the translocation of their active forms into the nucleus and their binding to specific DNA sequences via the ELISA assay. The expression of NF-κB and Nrf2 target genes was evaluated by R-T PCR and Western blot analysis. The conjugation of IND or DCL with OAO derivatives increased cytotoxicity and their effect on the tested signaling pathways. The most effective compound was the DCL hybrid with OAO morpholide (4d). This compound significantly reduced the activation and expression of NF-κB and enhanced the activation and expression of Nrf2. Increased expression of Nrf2 target genes led to reduced ROS production. Moreover, MAPKs and the related pathways were also affected. Therefore, conjugate 4d deserves more comprehensive studies as a potential PC therapeutic agent.
Insights
New drug conjugates combining NSAIDs with oleanolic acid derivatives show promise for pancreatic cancer therapy. The most effective compound suppressed key inflammation pathways and reduced oxidative stress in cancer cells.
Area of Science:
- Pharmacology
- Oncology
- Molecular Biology
Background:
- Nonsteroidal anti-inflammatory drugs (NSAIDs) coupled with oleanolic acid (OA) derivatives enhance anti-inflammatory activity in human hepatoma cells.
- Investigating the impact of these conjugates on signaling pathways in human pancreatic cancer (PC) cells is crucial for therapeutic development.
Purpose of the Study:
- To evaluate the effects of OA oxime (OAO) derivatives conjugated with NSAIDs (indomethacin/diclofenac) on inflammation signaling pathways in human pancreatic cancer (PC) cells.
- To assess the impact on nuclear factor-kappa B (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), and mitogen-activated protein kinase (MAPK) pathways.
Main Methods:
- Human pancreatic cancer (PSN-1) cells were treated with OAO derivatives and their NSAID conjugates.
- NF-κB and Nrf2 activation was measured via ELISA, assessing nuclear translocation and DNA binding.
- Gene and protein expression of NF-κB, Nrf2, and their target genes were analyzed using R-T PCR and Western blot.
Main Results:
- Conjugation of NSAIDs with OAO derivatives enhanced cytotoxicity and modulated key signaling pathways.
- The diclofenac (DCL) hybrid with OAO morpholide (4d) demonstrated significant efficacy.
- Compound 4d reduced NF-κB activation/expression while enhancing Nrf2 activation/expression, leading to decreased reactive oxygen species (ROS) production and affecting MAPK pathways.
Conclusions:
- The DCL-OAO morpholide conjugate (4d) exhibits potent anti-cancer effects by targeting inflammation and oxidative stress pathways in pancreatic cancer cells.
- Compound 4d warrants further investigation as a potential therapeutic agent for pancreatic cancer.
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