Antiproliferative effects, mechanism of action and tumor reduction studies in a lung cancer xenograft mouse model of an organometallic gold(<scp>i</scp>) alkynyl complex

Organometallic complexes offer a wide range of properties like structural variety, reaction kinetics, tunable lipophilicity and alternate mechanisms of activation under physiological conditions compared to platinum chemotherapeutics and are thus being explored for their potential anticancer applications. In this regard, gold(i) organometallics hold a pivotal position for their ability to act on biological targets different from DNA (which is the primary target of platinum therapeutics), such as thioredoxin reductase. Here, we report on the stability, <i>in vitro</i> antiproliferative effects, protein binding, cellular uptake, mechanism of action, effects on mitochondrial respiration of cancer cells as well as <i>in vivo</i> tolerance, toxicity and tumor reduction in an A549 lung cancer xenograft mouse model of an organometallic gold(i) complex (1) bearing 4-ethynylanisole and triethylphosphane as ligands. The complex, which was stable in DMSO and reactive towards <i>N</i>-acetylcysteine, triggered strong antiproliferative effects in various cancer cell lines and had a protein binding of approximately 65% that reduced its generally efficient uptake into tumor cells. Antimetastatic properties were indicated for 1 in a scratch assay and strong inhibition of thioredoxin reductase (TrxR) was confirmed for the purified enzyme as well as in A549 lung cancer cells, which strongly overexpress TrxR. Real time monitoring of the oxygen consumption rate in multiple cancer cell lines, using the Seahorse Mito stress assay, demonstrated that mitochondrial respiration was severely disrupted, showing a significantly low oxygen consumption rate. Other respiratory parameters, such as proton efflux, spare respiratory capacity and maximal respiration, were also attenuated upon treatment with 1. The complex was well tolerated <i>in vivo</i> in mice at a dose of 10 mg kg^-1 and showed tumor reduction compared to the control group of animals in a lung cancer xenograft model of nude mice. In summary, complex 1 represents a novel organometallic anticancer drug candidate with a mechanism related to TrxR inhibition and mitochondrial respiration inhibition, showing efficient <i>in vivo</i> antitumor efficacy.