Integrative chemoproteomics reveals anticancer mechanisms of silver(i) targeting the proteasome regulatory complex.

Silver compounds have favorable properties as promising anticancer drug candidates, such as low side effects, anti-inflammatory properties, and high potential to overcome drug resistance. However, the exact mechanism by which Ag(i) confers anticancer activity remains unclear, which hinders further development of anticancer applications of silver compounds. Here, we combine thermal proteome profiling, cysteine profiling, and ubiquitome profiling to study the molecular mechanisms of silver(i) complexes supported by non-toxic thiourea (TU) ligands. Through the formation of AgTU complexes, TU ligands deliver Ag+ ions to cancer cells and tumour xenografts to elicit inhibitory potency. Our chemical proteomics studies show that AgTU acts on the ubiquitin-proteasome system (UPS) and disrupts protein homeostasis, which has been identified as a main anticancer mechanism. Specifically, Ag+ ions are released from AgTU in the cellular environment, directly target the 19S proteasome regulatory complex, and may oxidize its cysteine residues, thereby inhibiting proteasomal activity and accumulating ubiquitinated proteins. After AgTU treatment, proteasome subunits are massively ubiquitinated and aberrantly aggregated, leading to impaired protein homeostasis and paraptotic death of cancer cells. This work reveals the unique anticancer mechanism of Ag(i) targeting the 19S proteasome regulatory complex and opens up new avenues for optimizing silver-based anticancer efficacy.

An Antitumor Bis(N-Heterocyclic Carbene)Platinum(II) Complex That Engages Asparagine Synthetase as an Anticancer Target.

New anticancer platinum(II) compounds with distinctive modes of action are appealing alternatives to combat the drug resistance and improve the efficacy of clinically used platinum chemotherapy. Herein, we describe a rare example of an antitumor PtII complex targeting a tumor-associated protein, rather than DNA, under cellular conditions. Complex [(bis-NHC)Pt(bt)]PF6 (1 a; Hbt=1-(3-hydroxybenzo[b]thiophen-2-yl)ethanone) overcomes cisplatin resistance in cancer cells and displays significant tumor growth inhibition in mice with higher tolerable doses compared to cisplatin. The cellular Pt species shows little association with DNA, and localizes in the cytoplasm as revealed by nanoscale secondary ion mass spectrometry. An unbiased thermal proteome profiling experiment identified asparagine synthetase (ASNS) as a molecular target of 1 a. Accordingly, 1 a treatment reduced the cellular asparagine levels and inhibited cancer cell proliferation, which could be reversed by asparagine supplementation. A bis-NHC-ligated Pt species generated from the hydrolysis of 1 a forms adducts with thiols and appears to target an active-site cysteine of ASNS.