Proteasome versus Thioredoxin Reductase Competition as Possible Biological Targets in Antitumor Mixed Thiolate-Dithiocarbamate Gold(III) Complexes

Abstract

New mixed gold(III) derivatives with dithiocarbamate and thiolate ligands have been synthesized and characterized. They display high anticancer activity against colon cancer cell lines without affecting to differentiated enterocytes, high stability in phosphate-buffered saline solution, and resistance to gold reduction in the presence of reducing agents in the majority of the derivatives. Some of them show interaction with thioredoxin reductase as derived from in vitro analysis and computational studies. However, a competition between this enzyme and proteasome is detected in cells, which is corroborated by the determination of proteasomal chymotrypsin-like activity inhibition. In addition, some of these dithiocarbamate gold(III) derivatives reduce cell viability and proliferation by intrinsic apoptotic pathway, with changes in mitochondrial membrane potential, cytochrome c release and caspase-3 activation. Consequently, our results show new complexes with proteasome as possible target in colorectal cancer.

Potent In Vitro and In Vivo Anticancer Activity of New Bipyridine and Bipyrimidine Gold (III) Dithiocarbamate Derivatives

“…Cancer cells produce anti-apoptotic and pro-survival proteins, and their treatment with proteasome inhibitors causes cell cycle arrest or apoptosis, suggesting their use in clinic [31]. Some gold (III) complexes have already been found to target the proteasome in cancer cells [8,12,17,20,32,33], and here we found that C6 inhibited proteasome activity in prostate cancer cells.…”

Synthesis of New Thiourea-Metal Complexes with Promising Anticancer Properties

“…For this reason, ligands with biological interest have been chosen to achieve an effective interaction with gold atom. Hence, thiolate [31,32], dithiocarbamate [33,34], phosphine [35,36], or N-heterocyclic carbene [20,[37][38][39][40] ligands, among others, have been at the center of study in the last two decades, showing good biological results (Figure 1).…”

Multifunctional AuI‐based AIEgens: Manipulating Molecular Structures and Boosting Specific Cancer Cell Imaging and Theranostics

“…Because the phosphine ligand of complex 1 and the chlorido ligand of 2a are presumably replaced before or upon interaction with the enzyme,a nd the cationic (NHC)-Au + fragments can be considered as the relevant moiety for target-drug interaction. [22,23,24] Thus,w ec ompared the binding poses and the interactions of fragments (TPE-NHC)Au + and ( i Pr 2 Ph) 2 -NHC)Au + in the binding pocket of human thioredoxin reductase (hTrxR, PDB ID:2 ZZB). [23] Thef ragments (TPE-NHC)Au + and ( i Pr 2 Ph) 2 -NHC)Au + were docked into the binding site and the Au atoms of them were predicted to interact with Cys498 of the enzyme.…”