Novel Phosphanegold(Ⅰ) Thiolate Complexes Suppress De Novo Lipid Synthesis To Promote Apoptosis In Human Lung Cancer

Background: Globally,the incidence of lung cancer continues to rise and the relative mortality rate is extremely high with newly reported five-year survival rate for all-type lung cancer is only 21%.The latest global cancer map showed that by 2020,lung cancer is one of the most common cancers after breast cancer,and the mortality rate of lung tumor patients is the top among all malignant cancers.At present,even though the clinical treatment of lung cancer is based on surgery combined with radiotherapy,chemotherapy,molecular targeted therapy and immunotherapy,the prognosis of these patients has not improved.Effective novel treatments for lung cancer are urgently required.Previous studies have shown that gold complexes are promising antitumor agents with significant effects both in vivo and in vitro.Methods: According to the chemical structure of auranofin,novel phosphanegold(Ⅰ)thiolate derivatives were synthesized,and the anti-tumor effect and potential mechanism of the new derivatives were tested through a series of cell experiments and animal tumor xenograft experiments.Results: In cell experiments,CCK-8 and colony formation assays were used to detect that the complexes had obvious inhibitory effects on the growth of three lung cancer cell lines(PC9,A549,H1299).Annexin V-FITC/PI double-stained flow cytometry was used to detect that the complexes promoted the apoptosis of lung cancer cells,and Transwell assay determined that the complexes inhibited the migration of lung cancer cells.phosphanegold(Ⅰ)thiolate derivatives significantly inhibited the activity of thioredoxin reductase,resulting in a significant increase in intracellular reactive oxygen species,damage to the structure and function of intracellular mitochondria,and promotion of apoptosis.On the other hand,phosphanegold(Ⅰ)thiolate derivatives inhibit the key enzymes of de novo lipid synthesis in tumor cells(sterol regulatory element binding transcription factor 1(SREBF1),fatty acid synthase(FASN)and adenosine triphosphate citrate lyase(ACLY)),blocking the synthesis of endogenous lipid fatty acids and phospholipids,resulting in decreased intracellular lipid storage,unable to provide sufficient energy supply and material structural support,thereby inducing apoptosis.In animal experiment,it was found that the mice in the intraperitoneal administration of phosphanegold(Ⅰ)thiolate derivatives had slow tumor growth and the final tumor size and weight were lower than those of the control group.Compared to the control group,the contents of fatty acids and phospholipids in the tumors of the mice treated with phosphanegold(Ⅰ)thiolate derivatives were significantly reduced,and the expressions of relative enzymes related to de novo lipid synthesis were significant reduced.Conclusion: A series of novel phosphanegold(Ⅰ) thiolate derivatives were designed and synthesized.Various cell experiments were carried out on the new phosphanegold(Ⅰ)thiolate derivatives,and the results showed that they have obvious tumor-inhibiting effects.Novel phosphanegold(Ⅰ)thiolate complexes significantly inhibited the activity of thioredoxin reductase 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 SREBF1、FASN and ACLY,thus reducing endogenous fatty acid and phospholipid synthesis.Both approaches suppressed lipid droplet storage and ultimately induced apoptosis in lung cancer cells.