Investigation of the anticancer efficacy and impact on energy metabolism of dual-core gold(i) complex BGC2a†

Dual-core gold(I) complex BGC2a has been shown to have superior anticancer potential to the clinical candidate auranofin (AF) in non-small lung cancer cells in vitro and in vivo. In this work, we further investigate BGC2a's potential as an anticancer candidate in a set of different cancer cell lines as well as its safety profile in normal cells. BGC2a (IC₅₀ ranging from 0.33 to 0.78 μM) consistently showed higher cytotoxicity in six cancer cell lines than AF (IC₅₀ ranging from 0.56 to 1.41 μM), without increasing its toxic effects in normal HS-5 and natural killer T (NKT) cells. BGC2a preferably killed KRAS-on cells over KRAS-off cells, and it was highly potent in inhibiting cancer stem-like cells, as it alone or combined with celecoxib reduced the colony formations of DLD1, PANC1, and A549 cells in a dose-dependent manner. Similar colony-suppressing effects were also identified in glioma stem cells GSC11 and GSC23. Pretreatment of BGC2a (1 μM, 24 h) could significantly inhibit the tumor formation in vivo. The mechanistic study indicated that BGC2a preferably inhibited the TrxR activity in mitochondria, and it reduced lactate production, which was mediated partially by inhibiting GAPDH. BGC2a induced apoptosis of HCT116 cells via a mitochondria-mediated mechanism and reduced the tumor growth of the HCT116 xenograft model without altering the body weight of treated mice. These findings further support BGC2a as a promising novel therapy for cancer treatment.