Piperine induces cellular stresses, apoptosis, and cytotoxicity via JNK signaling and has concentration-dependently additive or synergistic effects with sorafenib in hepatocellular carcinoma: an in-vitro study

• Published in: Naunyn-Schmiedeberg's archives of pharmacology 2024-12
• Main Authors: Sayilan Ozgun, Gulben, Ozgun, Eray, Karabas, Tugce, Suer Gokmen, Selma, Eskiocak, Sevgi
• Format: Article
• Language: English
• ISSN: 1432-1912; 1432-1912
• DOI: 10.1007/s00210-024-03725-0

We aimed to determine the effects of piperine on cell viability, cellular stresses, and apoptosis first, then the relationship of piperine's effects with the c-Jun N-terminal kinase (JNK) signaling pathway, and also the interaction of piperine with sorafenib in hepatocellular carcinoma. Hepatocellular carcinoma (HepG2 and Hep3B) and non-cancerous hepatocyte (AML12) cell lines were used. The cell viability was determined by using MTT assay. Cellular stresses, apoptosis, and JNK signaling markers were measured by Western blotting. Cells were pre-treated with SP600125 as a JNK inhibitor. The inhibitory concentration 50% (IC50) values and interaction of piperine with sorafenib were calculated by using CompuSyn software. IC50 values of piperine were 97 µM for HepG2, 58 µM for Hep3B, and 184 µM for AML12 with incubation for 48 h. Piperine caused a significant concentration-dependent increase in cellular stresses, apoptosis, and activated JNK signaling in hepatocellular carcinoma cells. Pre-treatment with a JNK inhibitor significantly reduced piperine-induced cellular stresses, apoptosis, and cytotoxicity. Piperine had concentration-dependent additive or synergistic effects when combined with sorafenib in both HepG2 and Hep3B cells. We found that piperine induces cellular stresses, apoptosis, and cytotoxicity via JNK signaling and has concentration-dependently additive or synergistic effects with sorafenib in hepatocellular carcinoma.