Novel gold-based complex GC7 suppresses cancer cell proliferation via impacting energy metabolism mediated by mitochondria

Due to their pivotal roles in regulating energy metabolism and apoptosis, mitochondria in cancer cells have been considered a vulnerable and feasible target. Many anticancer agents, e.g., metal-based compounds, are found to target and disturb mitochondria primarily, which may lead to the disturbance of energy metabolism and, more importantly, the initiation of apoptosis. In this work, a gold-based complex 7 (GC7) was synthesized and evaluated in a series of different cancer cell lines. The anticancer efficacies of GC7 on cell viability, apoptosis, and colony formation were determined. Cellular thioredoxin reductase (TrxR) activity, oxygen consumption rate (OCR), glucose uptake, and lactate production following GC7 treatment were evaluated and analyzed. The Jeko-1 and A549 xenograft models were used to assess GC7’s tumor-suppressing effects. The results showed that GC7 possessed a broad-spectrum anticancer effect, with IC₅₀ values ranging from 0.43 to 1.2 μM in multiple cancer cell lines, which was more potent than gold-based auranofin (∼2–6 folds). GC7 (0.3 and 1 μM) efficiently induced apoptosis of Jeko-1, A549, and HCT116 cells, and it suppressed the sphere formation of cancer stem cells GSC11 and GSC23 cells at 0.1 μM, and it completely eliminated colony at 0.3 μM. The preliminary mechanistic study showed that GC7 inhibited cellular TrxR activity, suppressed mitochondrial OCR, reduced mitochondrial membrane potential (MMP), decreased glucose uptake, and possibly suppressed glycolysis to reduce lactate production. GC7 was predicted to have a similar yet slightly different pharmacokinetic profile as auranofin. Finally, GC7 (20 mg/kg, oral, 5/week, or 3 mg/kg, IP, 3/week) significantly inhibited tumor growth. In conclusion, GC7 showed great potential in suppressing cancer cell proliferation, probably via inhibiting TrxR and impacting mitochondria-mediated energy metabolism.