Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and third leading cause of cancer deaths worldwide due to late symptom presentation and ineffective treatments. Currently, tyrosine kinase inhibitors Sorafenib and Lenvatinib are the only FDA-approved first-line treatment for HCC patients. Cancer cells experience distinctly high amount of oxidative stress compared to normal cells. Reactive oxygen species (ROS) are by-products of metabolism. However, cancer cells’ metabolic activities are hyper-activated as they have greater demands for energy, thereby also resulting in greater amounts of ROS generated. Besides, oncogenes and properties of the tumor microenvironment like ER stress and hypoxia also contribute to ROS generation in cancer cells. With higher concentrations of ROS, cancer cells also have increased antioxidant production capacity to counteract ROS. NADPH is a major metabolite and antioxidant immensely generated by cancer cells. In human HCC, our group previously found the pentose phosphate pathway and folate cycle to be major metabolic pathways of NADPH production. The thioredoxin system is a ubiquitous mammalian antioxidant system that is activated by the antioxidant system-activating electron donor NADPH. Thioredoxin reductase 1 (TXNRD1) is the sole activating-enzyme of the thioredoxin system through transmission of electron from NADPH to TXN, the ROS-scavenging member of the thioredoxin system. TXNRD1 is imperative for maintenance of intracellular redox homeostasis as confirmed when NRF2 was found to be the transcription activator of TXNRD1. Overexpression of TXNRD1 was found in human HCC with significant correlations with poor clinical prognosis and patient survival. Altogether, these findings are indicative of redox balance being vital for HCC growth. Loss-of-function studies utilizing shRNA-mediated inhibition of TXNRD1 resulted in significant induction of oxidative stress which suppressed HCC growth. The resulting oxidative stress also sensitized HCC cells towards its conventional therapeutic Sorafenib. Translationally, pharmacological TXNRD1 inhibitor auranofin (AUR) also induced oxidative stress which greatly sensitized HCC cells towards Sorafenib. Synergism between AUR and Sorafenib was observed as oxidative stress accumulations dramatically induced apoptosis in vitro and suppressed tumor formation in vivo. Our investigation demonstrated oxidative stress induction through inhibition of the thioredoxin system sensitized HCC cells towards conventional therapeutics. Combination of TXNRD1 inhibitor AUR and Sorafenib represents a novel treatment regimen, with enhanced efficacy, for HCC patients.

Citation Format: Derek Lee, Iris Ming-Jing Xu, David Kung-Chun Chiu, Robin Kit-Ho Lai, Chun-Ming Wong, Irene Oi-Lin Ng, Carmen Chak-Lui Wong. Thioredoxin system inhibition using auranofin represents a new therapeutic approach for hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 882.

©2019 American Association for Cancer Research.
2019
American Association for Cancer Research.