A soluble bis-chelated gold(I) diphosphine compound with strong anticancer activity and low toxicity.
Gold-containing compounds have shown anticancer potential, but their clinical applications have been severely limited by poor stability and high toxicity in vivo. Here, we report a novel soluble bis-chelated gold(I)-diphosphine compound (GC20) with strong anticancer activity and low toxicity. GC20 shows strong antiproliferation potency against a broad spectrum of cancer cell lines including cisplatin-resistant cancer cells (IC50 ≈ 0.5 μM) and significantly reduces tumor growth in several tumor xenografts in mouse models at doses as low as 2 mg/kg. Studies of its mechanism revealed that GC20 specifically inhibits the enzymatic activity of thioredoxin reductase by binding to selenocysteine residue, without targeting other well-known selenol and thiol groups contained in biomolecules. Remarkably, in animal studies GC20 was shown to be well tolerated even at the high dose of 8 mg/kg. Our results strongly suggest that GC20 represents a promising candidate for the development of novel anticancer drugs.
School of Pharmacy, Shanghai Jiao Tong University, 800 Dong Chuan Road, Shanghai 200240, China.
Yanli
Y
Wang
Minyu
M
Liu
Ran
R
Cao
Wanbin
W
Zhang
Ming
M
Yin
Xuhua
X
Xiao
Quanhai
Q
Liu
Niu
N
Huang
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006046:Gold; D006801:Humans; D007928:Lethal Dose 50; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010720:Phosphines / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D013329:Structure-Activity Relationship; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D056831:Coordination Complexes; D010720:Phosphines; D006046:Gold; D013880:Thioredoxin-Disulfide Reductase; D005978:Glutathione; D002945:Cisplatin