Ruthenium polypyridyl complexes as inducer of ROS-mediated apoptosis in cancer cells by targeting thioredoxin reductase

Abstract

TrxR is an NADPH-dependent selenoenzyme upregulated in a number of cancers. It plays a pivotal role in cancer progression and represents an increasingly attractive target for anticancer drugs. The limitations of cisplatin in cancer treatment have motivated the extensive investigation to other metal complexes, especially ruthenium (Ru) complexes. In this study, we present the in vitro biological evaluation of four Ru(II) polypridyl complexes with diimine ligands, namely, [Ru(bpy)3](2+) (1), [Ru(phen)3](2+) (2), [Ru(ip)3](2+) (3), [Ru(pip)3](2+) (4) (bpy = 2,2′-bipyridine, phen = 1,10-phenanthroline, ip = imidazole[4,5-f][1,10]phenanthroline, pip = 2-phenylimidazo[4,5-f][1,10]phenanthroline), and demonstrate that they exhibit antiproliferative activities against A375 human melanoma cells through inhibition of TrxR. As the planarity of the structure increases, their TrxR-inhibitory effects and in vitro anticancer activities were enhanced. Among them, complex 4 exhibited higher antiproliferative activity than cisplatin, and the TrxR-inhibitory potency of 4 was more effective than auranofin, a positive TrxR inhibitor. Complex 4 suppressed the cancer cell growth through induction of apoptosis as evidenced by accumulation of sub-G1 cell population, DNA fragmentation and nuclear condensation. Moreover, complex 4 was able to localize in mitochondria and therein induced ROS-dependent apoptosis by inhibition of TrxR activity. Activation of MAPKs, AKT, DNA damage-mediated p53 phosphorylation and inhibition of VEGFR signaling were also triggered in cells exposed to complex 4. On the basis of this evidence, we suggest that Ru polypyridyl complexes could be developed as TrxR-targeted agents that demonstrate application potentials for treatment of cancers.

Monomeric and dimeric coordinatively saturated and substitutionally inert Ru(ii) polypyridyl complexes as anticancer drug candidates

“…In addition, no luminescence was found when 104 was incubated with the selenopeptide. 147 The authors could also demonstrate that the inhibition of TrxR then promoted the generation and accumulation of ROS, leading to cell apoptosis through the activation of mitochondrial pathway. 147 However, since the complex is substitutionally inert, coordination of the metal seems impossible.…”

“…147 The authors could also demonstrate that the inhibition of TrxR then promoted the generation and accumulation of ROS, leading to cell apoptosis through the activation of mitochondrial pathway. 147 However, since the complex is substitutionally inert, coordination of the metal seems impossible. Unfortunately, no further information is available about the suggested covalent adduct which must occur between the ligand of complex 104 and the selenol.…”

“…To confirm this hypothesis, a photophysical study of complex 104 was carried out in the presence of the selenopeptide under physiological conditions (at 37°C in PBS buffer). 147 The results showed a concomitant disappearance of the absorption band of complex 104 and the rise of a new one centred at 497 nm. In addition, no luminescence was found when 104 was incubated with the selenopeptide.…”

“…On the other hand, the most lipophilic compound (104) had the greatest TrxR inhibitory potency. 147 The mechanism of action suggested by these researchers considered…”

“…147 The thioredoxin system, which is composed of thioredoxin (Trx), TrxR and NADPH, has been intensively considered as an interesting target in anticancer research over the last five years. It has a key role in regulating redox balance and intracellular signalling pathways.…”