Induction of Apoptosis by Coptisine in Hep3B Hepatocellular Carcinoma Cells through Activation of the ROS-Mediated JNK Signaling Pathway

Abstract

Hepatocellular carcinoma (HCC) has a high mortality rate worldwide, and treatment is very limited due to its high recurrence and low diagnosis rate, and therefore there is an increasing need to develop more effective drugs to treat HCC. Coptisine is one of the isoquinoline alkaloids, and it has various pharmacological effects. However, the evidence for the molecular mechanism of the anticancer efficacy is still insufficient. Therefore, this study investigated the antiproliferative effect of coptisine on human HCC Hep3B cells and identified the action mechanism. Our results showed that coptisine markedly increased DNA damage and apoptotic cell death, which was associated with induction of death receptor proteins. Coptisine also significantly upregulated expression of proapoptotic Bax protein, downregulated expression of anti-apoptotic Bcl-2 protein, and activated caspase-3, -8, and -9. In addition, coptisine remarkably increased the generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential (MMP), and release of cytochrome c into the cytoplasm. However, N-acetylcysteine (NAC), a ROS scavenger, significantly attenuated the apoptosis-inducing effect of coptisine. It is worth noting that coptisine significantly upregulated phosphorylation of ROS-dependent c-Jun N-terminal kinase (JNK), whereas treatment with JNK inhibitor could suppress an apoptosis-related series event. Taken together, our results suggest that coptisine has an anticancer effect in Hep3B cells through ROS-mediated activation of the JNK signaling pathway.

Isoquinoline Alkaloids from Coptis chinensis Franch: Focus on Coptisine as a Potential Therapeutic Candidate against Gastric Cancer Cells

“…The IC 50 values obtained in our studies were significantly lower than those presented in published reports for osteosarcoma (12.99–28.54 µM), pancreatic (100 µM), as well as for lung cancer (18.09–21.60 µM) [ 58 , 59 , 60 ]. In agreement with previous findings [ 59 , 61 , 62 ], triggering of apoptosis was found to be an important mechanism in the antiproliferative activity of 11 against lung, hepatocellular and colon cancer cells. The induction of apoptosis by 11 was characterized by, among others, the activation of caspase-3, the cleavage of poly adenosine diphosphate ribose polymerase, the upregulation expression of pro-apoptotic Bax protein and the downregulation of the expression of anti-apoptotic Bcl-2 protein.…”

ROS-Mediated Anti-Tumor Effect of Coptidis Rhizoma against Human Hepatocellular Carcinoma Hep3B Cells and Xenografts

“…Major phytochemicals with anticancer activity contained in Coptidis Rhizoma include isoquinoline alkaloids such as berberine, coptisine, and palmatine [ 10 , 11 ], and it was confirmed by HPLC analysis that the CR used in this study also contained these compounds. Although there have been reports that these alkaloids inhibit the proliferation of HCC cells and promote apoptosis [ 32 , 33 ], there has been no investigation of the anti-cancer activity of the Coptidis Rhizoma extract itself against HCC cells. Therefore, our results support the results of previous studies demonstrating the anti-cancer activity of Coptidis Rhizoma against HCC.…”

An IBD-associated pathobiont synergises with NSAID to promote colitis which is blocked by NLRP3 inflammasome and Caspase-8 inhibitors

“…Indeed, cleaved N4BP1 was only detected in AIEC/piroxicam combination group (Figure S1D). Since Caspase-8 can control apoptosis by activating Caspase-3 by cleaving it (Kim et al, 2020), we assayed for its cleaved expression and found it to be highly expressed in AIEC/piroxicam group when compared to AIEC or piroxicam only groups (Figure 1G). A similar cleavage in PARP was also observed in the AIEC/piroxicam group (Figure 1G).…”