Novel phosphanegold(I) thiolate complexes suppress de novo lipid synthesis in human lung cancer

Abstract

The upregulation of lipid metabolism is considered one of the most common characteristic changes in tumor cells. In this study, the effects of phosphanegold(I) thiolate complexes on the regulation of lipid metabolism in lung cancer cells were investigated. Six novel phosphanegold(I) thiolate complexes capable of inhibiting lung cancer cell growth both in vitro and in vivo were synthesized and characterized. These complexes significantly inhibited the activity of thioredoxin reductases and impaired the normal structure and function of mitochondria, leading to an accumulation of internal reactive oxygen species. In addition, they markedly inhibited key enzymes involved in de novo lipid synthesis, including sterol regulatory element-binding proteins, fatty acid synthase, and adenosine triphosphate citrate lyase, thus reducing endogenous fatty acid and phospholipid synthesis. Both approaches suppressed lipid droplets storage and ultimately induced apoptosis in lung cancer cells. Interestingly, pretreatment with N-acetyl-l-cysteine and free fatty acids partially reversed the inhibitory effect of phosphanegold(I) thiolate complexes on lung cancer cells. These results are the first to indicated that gold(I) complexes are promising candidates for targeting lipid metabolism in lung cancer treatment strategies.