Development of lactobionic acid conjugated-copper chelators as anticancer candidates for hepatocellular carcinoma

Abstract

Hepatic copper deposition leads to metabolic disorders, rapid increase in reactive oxygen species (ROS) levels, and even the occurrence and metastasis of hepatocellular carcinoma. Copper chelation or copper transporter inhibition have already been developed into an effective method to control the canceration of hepatocytes and kill the hepatocarcinoma cells. Here, we designed three novel lactobionic acid conjugated copper chelators (GT1, 9 and 10), which have the potential to be recognized by asialoglycoprotein receptor (ASGPR), a high-capacity C-type lectin receptor selectively expressed in liver. Both GT1, 9 and 10 can selectively and efficiently coordinate with copper in solution and in the high-copper treated hepatocellular carcinomas model (HC HepG2 cells). The thiosemicarbazone-based chelator GT1 should more effectively eliminate copper and promote apoptosis of HC HepG2 cells, which might have application prospects in preventing cancerization and other pathological lesions caused by copper deposition of liver. Moreover, our results also revealed the potential of GT1 to be harnessed as preventive leading structures of the hepatocellular carcinomas.

Keywords

• Copper chelation
• Hepatocellular carcinoma
• Copper deposition
• Apoptosis
• Hepatic targeting