Gold (III) Derivatives in Colon Cancer Treatment

Cancer is one of the leading causes of morbidity and mortality worldwide. Colorectal cancer (CRC) is the third most frequently diagnosed cancer in men and the second in women. Standard patterns of antitumor therapy, including cisplatin, are ineffective due to their lack of specificity for tumor cells, development of drug resistance, and severe side effects. For this reason, new methods and strategies for CRC treatment are urgently needed. Current research includes novel platinum (Pt)- and other metal-based drugs such as gold (Au), silver (Ag), iridium (Ir), or ruthenium (Ru). Au(III) compounds are promising drug candidates for CRC treatment due to their structural similarity to Pt(II). Their advantage is their relatively good solubility in water, but their disadvantage is an unsatisfactory stability under physiological conditions. Due to these limitations, work is still underway to improve the formula of Au(III) complexes by combining with various types of ligands capable of stabilizing the Au(III) cation and preventing its reduction under physiological conditions. This review summarizes the achievements in the field of stable Au(III) complexes with potential cytotoxic activity restricted to cancer cells. Moreover, it has been shown that not nucleic acids but various protein structures such as thioredoxin reductase (TrxR) mediate the antitumor effects of Au derivatives. The state of the art of the in vivo studies so far conducted is also described.

Thymosin β4 Is an Endogenous Iron Chelator and Molecular Switcher of Ferroptosis

Thymosin β4 (Tβ4) was extracted forty years agofrom calf thymus. Since then, it has been identified as a G-actin binding protein involved in blood clotting, tissue regeneration, angiogenesis, and anti-inflammatory processes. Tβ4 has also been implicated in tumor metastasis and neurodegeneration. However, the precise roles and mechanism(s) of action of Tβ4 in these processes remain largely unknown, with the binding of the G-actin protein being insufficient to explain these multi-actions. Here we identify for the first time the important role of Tβ4 mechanism in ferroptosis, an iron-dependent form of cell death, which leads to neurodegeneration and somehow protects cancer cells against cell death. Specifically, we demonstrate four iron2+ and iron3+ binding regions along the peptide and show that the presence of Tβ4 in cell growing medium inhibits erastin and glutamate-induced ferroptosis in the macrophage cell line. Moreover, Tβ4 increases the expression of oxidative stress-related genes, namely BAX, hem oxygenase-1, heat shock protein 70 and thioredoxin reductase 1, which are downregulated during ferroptosis. We state the hypothesis that Tβ4 is an endogenous iron chelator and take part in iron homeostasis in the ferroptosis process. We discuss the literature data of parallel involvement of Tβ4 and ferroptosis in different human pathologies, mainly cancer and neurodegeneration. Our findings confronted with literature data show that controlled Tβ4 release could command on/off switching of ferroptosis and may provide novel therapeutic opportunities in cancer and tissue degeneration pathologies.

TXNRD3 supports male fertility via the redox control of spermatogenesis

Thioredoxin/glutathione reductase (TGR, TXNRD3) is a thiol oxidoreductase of unknown function composed of thioredoxin reductase and glutaredoxin domains. This NADPH-dependent enzyme evolved by gene duplication within the Txnrd family, is expressed in the testes and can reduce both thioredoxin and glutathione in vitro. To characterize the function of TXNRD3 in vivo, we generated a strain of mice with the deletion of Txnrd3 gene. We show that Txnrd3 knockout mice are viable and without discernable gross phenotypes, but TXNRD3 deficiency leads to fertility impairment in male mice. Txnrd3 knockout animals exhibit a lower fertilization rate in vitro, a sperm movement phenotype and an altered redox status of thiols. Proteomic analyses revealed a broad range of substrates reduced by TXNRD3 during sperm maturation, presumably as a part of quality control. The results show that TXNRD3 plays a critical role in male reproduction via the thiol redox control of spermatogenesis.

Exercise Reduces the Protein Abundance of TXNIP and Its Interacting Partner REDD1 in Skeletal Muscle: Potential Role for a PKA-Mediated Mechanism

Thioredoxin-interacting protein (TXNIP) negatively effects the redox state and growth signaling via its interactions with thioredoxin (TRX) and regulated in development and DNA damage response 1 (REDD1), respectively. TXNIP expression is downregulated by pathways activated during aerobic exercise (AE), via posttranslational modifications (PTMs; serine phosphorylation and ubiquitination). The purpose of this investigation was to determine the effects of acute AE on TXNIP expression, posttranslational modifications, and its interacting partners, REDD1 and TRX. Fifteen healthy adults performed 30 minutes of aerobic exercise (80% VO2max) with muscle biopsies taken before, immediately following, and three hours following the exercise bout. To explore potential mechanisms underlying our in vivo findings, primary human myotubes were exposed to two models of exercise, electrical pulse stimulation (EPS) and palmitate-forskolin-ionomycin (PFI). Immediately following exercise, TXNIP protein decreased, but returned to pre-exercise levels three hours post exercise. These results were replicated in our PFI exercise model only. Although not statistically significant, there was a trending main effect in serine-phosphorylation status of TXNIP (p=0.07) immediately following exercise. REDD1 protein decreased three hours after exercise. AE had no effect on TRX protein expression, gene expression or the activity of its reducing enzyme, thioredoxin reductase. Consequently, AE had no effect on the TRX: TXNIP interaction. Our results indicate that AE leads to acute reductions in TXNIP and REDD1 protein expression. However, these changes did not result in alterations in the TRX: TXNIP interaction and could not be entirely explained by alterations in TXNIP PTMs or changes in TRX expression or activity.

Oridonin induces oxidative stress-mediated cancer cells apoptosis via targeting thioredoxin reductase

Background: Thioredoxin reductase (TrxR) plays vital role in regulating cellular redox balance as well as redox-mediated signal transduction. Accumulating evidence supports that overactivation of TrxR is closely related to tumorigenesis and that targeting TrxR ablation reverses the growth of numerous malignant tumors, making TrxR a promising target for cancer chemotherapy. Thus, the discovery and development of molecules as promising anticancer agents that target TrxR is of great significance. Oridonin was shown to inhibit TrxR activity, but the detailed cellular mechanism is largely unknown. Objective: The study investigated the mechanism of action and underlying inhibitory properties of oridonin on TrxR in HeLa cells. Methods: A covalent docking was performed to reveal the possible interaction between oridonin and TrxR by Schrödinger Software Suite. TrxR activity was determined by 5,5’-dithiobis-2-nitrobenzoic acid reduction assay and endpoint insulin reduction assay. Sulforhodamine B and colony formation assay were employed to assess the viability and growth of cells. Reactive oxygen species level was measured by probe 2’, 7’-dichlorfluorescein diacetate, and dihydroethidium. Hoechst 33342 staining, caspase 3 activation, and fluorescein-5-isothiocyanate-conjugated Annexin V and propidium iodide double staining were used to evaluate apoptosis. Results: Here, we reported the oridonin as a potent inhibitor of TrxR. Inhibition of TrxR results in a decrease of thiols content and total glutathione elevates reactive oxygen species levels, and finally promotes oxidative stress-mediated apoptosis of cancer cells. Conclusion : Targeting TrxR by oridonin discloses a novel molecular mechanism underlying the biological action of oridonin and sheds light on developing oridonin as a potential tumor therapeutic agent.

Computational Studies of Au(I) and Au(III) Anticancer MetalLodrugs: A Survey

Owing to the growing hardware capabilities and the enhancing efficacy of computational methodologies, computational chemistry approaches have constantly become more important in the development of novel anticancer metallodrugs. Besides traditional Pt-based drugs, inorganic and organometallic complexes of other transition metals are showing increasing potential in the treatment of cancer. Among them, Au(I)- and Au(III)-based compounds are promising candidates due to the strong affinity of Au(I) cations to cysteine and selenocysteine side chains of the protein residues and to Au(III) complexes being more labile and prone to the reduction to either Au(I) or Au(0) in the physiological milieu. A correct prediction of metal complexes’ properties and of their bonding interactions with potential ligands requires QM computations, usually at the ab initio or DFT level. However, MM, MD, and docking approaches can also give useful information on their binding site on large biomolecular targets, such as proteins or DNA, provided a careful parametrization of the metal force field is employed. In this review, we provide an overview of the recent computational studies of Au(I) and Au(III) antitumor compounds and of their interactions with biomolecular targets, such as sulfur- and selenium-containing enzymes, like glutathione reductases, glutathione peroxidase, glutathione-S-transferase, cysteine protease, thioredoxin reductase and poly (ADP-ribose) polymerase 1.

Ru(III) Complexes with Lonidamine-Modified Ligands

A series of bifunctional Ru(III) complexes with lonidamine-modified ligands (lonidamine is a selective inhibitor of aerobic glycolysis in cancer cells) was described. Redox properties of Ru(III) complexes were characterized by cyclic voltammetry. An easy reduction suggested a perspective for these agents as their whole mechanism of action seems to be based on activation by metal atom reduction. New compounds demonstrated a more pronounced antiproliferative potency than the parental drug; individual new agents were more cytotoxic than cisplatin. Stability studies showed an increase in the stability of complexes along with the linker length. A similar trend was noted for antiproliferative activity, cellular uptake, apoptosis induction, and thioredoxin reductase inhibition. Finally, at concentrations that did not alter water solubility, the selected new complex evoked no acute toxicity in Balb/c mice.