Metabolic Collapse in Pancreatic Cancer via Combined Inhibition of Lactate Export and Thioredoxin Reductase

Abstract

Pancreatic cancer is one of the most poorly prognosed types of cancer, with a low survival rate. Cancer cells exhibit altered and rapid metabolism, and in a process known as aerobic glycolysis, they metabolize glucose to lactate even in the presence of sufficient oxygen. Altered metabolism is a hallmark of cancer, making it a promising therapeutic target. There are many potential inhibitors of cancer cell metabolism, including auranofin and syrosingopine. Auranofin induces oxidative stress in cells by generating reactive oxygen species (ROS). Meanwhile, syrosingopine is an inhibitor of the two lactate transporters, MCT1 and MCT4, which contribute to intracellular acidification. Our studies demonstrated the high biological activity of the combination of auranofin and syrosingopine against pancreatic cancer in both in vitro and in vivo models. Our proposed mechanism of action for this drug combination is based on the simultaneous induction of oxidative stress and inhibition of lactate transporters, which consequently directs cancer cells to the apoptosis pathway.