Thioredoxin Reductase and Organometallic Complexes: A Pivotal System to Tackle Multidrug Resistant Tumors?

SIMPLE SUMMARY: The identification of biological targets is an essential step in deciphering the mechanism of action of anticancer drugs. In this review, we chose to study the relationship between the inhibition of thioredoxin reductase (TrxR), a key enzyme in maintaining the redox balance of cells, and the cytotoxic effects of two groups of organometallic complexes. The first group is essentially composed of Au(I) and Au(III) complexes and the second one comprises metallocifens (organometallic complexes derived from tamoxifen). The results show that these two groups interact differently with TrxR at the molecular level. Even if the contribution of TrxR inhibition to the cytotoxicity of complexes is clearly established for many of them, the number of complexes for which TrxR inhibition plays a predominant role appears quite limited. Eventually, the antiproliferative activity of most of the complexes appears to stem from the interaction with several targets, a favorable strategy to tackle MDR tumors. ABSTRACT: Cancers classified as multidrug-resistant (MDR) are a family of diseases with poor prognosis despite access to increasingly sophisticated treatments. Several mechanisms explain these resistances involving both tumor cells and their microenvironment. It is now recognized that a multi-targeting approach offers a promising strategy to treat these MDR tumors. Inhibition of thioredoxin reductase (TrxR), a key enzyme in maintaining redox balance in cells, is a well-identified target for this approach. Auranofin was the first inorganic gold complex to be described as a powerful inhibitor of TrxR. In this review, we will first recall the main results obtained with this metallodrug. Then, we will focus on organometallic complexes reported as TrxR inhibitors. These include gold(I), gold(III) complexes and metallocifens, i.e., organometallic complexes of Fe and Os derived from tamoxifen. In these families of complexes, similarities and differences in the molecular mechanisms of TrxR inhibition will be highlighted. Finally, the possible relationship between TrxR inhibition and cytotoxicity will be discussed and put into perspective with their mode of action.