Unlocking the Potential: Novel NSAIDs Hybrids Unleash Chemopreventive Power toward Liver Cancer Cells through Nrf2,...

Area of Science:

• Hepatocellular Carcinoma (HCC) research
• Drug discovery and development
• Molecular signaling pathways

Background:

• Hepatocellular carcinoma (HCC) is an aggressive cancer with limited therapeutic options.
• Non-steroidal anti-inflammatory drugs (NSAIDs) like Ibuprofen and Ketoprofen have shown some anti-cancer properties.
• Oleanolic acid oximes (OAO) derivatives offer a scaffold for novel drug design.

Purpose of the Study:

• To synthesize novel conjugates of NSAIDs (Ibuprofen, Ketoprofen) with OAO derivatives.
• To evaluate the activity of these conjugates in modulating signaling pathways crucial for HCC.
• To assess the cytotoxicity and therapeutic potential of these new compounds.

Main Methods:

• Synthesis of Ibuprofen-OAO and Ketoprofen-OAO conjugates.
• In vitro evaluation in normal THLE-2 liver cells and HCC-derived HepG2 cells.
• Analysis of key signaling pathways including Nrf2-ARE, NF-κB, MAPK (AKT, ERK, p38, JNK, p70S6K), STAT3, STAT5, and CREB.

Main Results:

• Conjugation reduced the cytotoxicity of parent NSAIDs in both cell lines.
• Conjugates modulated the Nrf2-ARE pathway differently in normal vs. HCC cells.
• Significant reduction in NF-κB, STAT3, STAT5, and CREB observed in HepG2 cells.
• MAPK signaling pathways were modulated by the conjugates.
• Conjugates with OAO-morpholide exhibited the highest activity.

Conclusions:

• IBU-OAO and KET-OAO conjugates effectively modulate key signaling pathways implicated in liver cancer.
• The specific effects on signaling pathways are structure-dependent.
• Reduced cytotoxicity and targeted pathway modulation suggest potential for HCC prevention.