Thioredoxin System Modulation by Plant and Fungal Secondary Metabolites

Thioredoxin (Trx) is the major cellular protein disulfide reductase in a broad range of organisms, including humans. Trx, together with glutaredoxin (Grx), plays critical roles in the regulation of cellular protein redox homeostasis. Reduced thioredoxin transfers reducing equivalents to disulphides in target proteins, leading to reversible oxidation of its active centre dithiol to a disulphide. The resulting disulphide bridge is, in turn, reduced to a dithiol by thioredoxin reductase (TrxR). Increasing attention has been paid to the role of Trx, as it has been shown to be a signalling intermediate beyond its intrinsic antioxidant activity. Indeed, this protein acts as a growth factor, activates a number of transcription factors regulating cell growth and survival, acts as cofactor for ribonucleotide reductase, and promotes angiogenesis. In addition, Trx has been demonstrated to cooperatively inhibit programmed cell death. Because of the multiple roles of Trx system in tumorigenesis, this protein represents an emerging target for anti-cancer drugs. Several Trx system modulators have been identified: a semi-synthetic Trx inhibitor, PX-12 (1-methylpropyl 2-imidazolyl disulfide), has been placed in a clinical trial. However, there is a growing interest in finding new selective ones. Natural products continue to provide structurally complex, but highly original lead structures for drug discovery programs: polyphenols, quinones, and terpenoids showed to affect the Trx/TrxR system at different levels. The purpose of this review is to provide an overview of the plant and fungal secondary metabolites interfering with Trx and TrxR activities, paying particularly attention to their mechanism of action. Among polyphenols, curcumin and some flavonoids such as myricetin and quercetin, have been identified as potential anticancer agents with a mechanism of action that may be mediated by the Trx system.