Abstract
Glibenclamide (Gli) is a widely employed drug in the treatment of type 2 diabetes and many lines of evidence have described its anti-tumor effects in some neoplasms. The aim of the present study was to investigate the effect of Gli on apoptosis of human hepatocellular carcinoma (HCC) cells and to analyze the underlying pathway involved in this action. Two HCC cell lines, HepG-2 and Huh7 were used as the cell models. We found that Gli treatment significantly inhibited cell viability, induced a significant cell-cycle arrest in G2/M-phase and induced apoptosis in both HepG-2 and Huh7 cells. We further verified that apoptosis induction by Gli was accompanied by increase in ROS levels and activation of the JNK pathway. Scavenging of the intracellular ROS with its blocker N-acetyl-L-cysteine (NAC) could mitigate the Gli-induced apoptosis and JNK activation in the two HCC cell lines. Furthermore, inhibition of JNK pathway by its inhibitor SP100625 effectively reduced Gli-induced apoptosis in HCC cells. In conclusion, Gli treatment significantly induced cell apoptosis by promoting ROS-dependent JNK pathway activation in HCC cells. Gli may be a potential clinical anti-tumor drug for HCC.
Highlights
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies and the third most common cause of cancer-related deaths in the world, accounting for 80–90% of all primary liver cancers [1]
In order to verify the effects of Gli on HCC cell survival, two HCC cell line, HepG-2 and Huh7 were treated with different concentrations of Gli for 24 h
Gli induces decline in cell viability, accompanied with cell apoptosis, reactive oxygen species (ROS) generation, and JNK activation [11]
Summary
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies and the third most common cause of cancer-related deaths in the world, accounting for 80–90% of all primary liver cancers [1]. The global incidence of HCC is predicted to keep rising over the few years, and studies for exploring more effective treatment options are quite urgent. The combination of unrestrained cell proliferation and impaired apoptosis plays a major role in the progression of HCC tumorigenesis. Known as programmed cell death, maintains the healthy survival/death balance in metazoan cells. It is executed by apoptotic proteins including released cytochrome c (Cyt-c) and the activated caspase-3 (cleaved caspase-3) through either extrinsic or intrinsic pathways [2]. Morphological hallmarks of apoptosis include cell shrinkage, chromatin condensation, and DNA fragmentation [3]. While defective apoptosis renders cancer cells resistant to treatment and promotes carcinogenesis
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