About this Research Topic
In recent years the efforts spent to repurpose old drugs for new clinical applications have led to the development of an alternative “Drug Repositioning” strategy as a promising and highly effective route for new drug discovery. As an example, Auranofin, an antiarthritic gold drug in clinical use since 1986, was found to also manifest relevant anticancer and antiparasitic properties and was recently admitted to some new clinical trials.
Despite the conspicuous number of published papers, the mechanism of action of auranofin (AF) is not fully understood. To date, it is commonly accepted that AF causes a dose-dependent inhibition on DNA, RNA, and protein synthesis at cytotoxic concentrations. However, it is known that only 1–10% of metallodrugs (e.g. cisplatin) accumulated in the cell can reach nuclear DNA. This fact is thought to be strictly correlated with the well-known chemotherapeutic side effects, as the remaining cytotoxic agent probably diffuses in the organism and produces systemic toxicity. In this view, proteins have attracted increasing interest as probable “alternative targets”. Indeed, the activity of AF also relies on inhibiting cell proliferation by induction of apoptotic cell death, which inhibits mitochondrial and cytosolic thioredoxin reductase and leads to oxidative stress.
Several studies have already highlighted the importance of gold compounds, either Au(I) or Au(III), as a promising class of cytotoxic agents with the potential of becoming effective anticancer or anti-infective candidates. Despite their pharmacological potential, the modes of action of these compounds are still largely unknown and a matter of intense research and debate. In the case of Au(I) compounds, mitochondria and pathways of oxidative phosphorylation are seen as the primary intracellular targets. Moreover, inhibition of the selenoenzyme thioredoxin reductase seems to be a common mechanistic trait to explain the action of these compounds, leading to apoptosis through activation of a mitochondrial pathway.
Nonetheless, the treatment with Au(I) complexes can led to some acquired chemoresistance associated with a low level of cross-resistance to the Au(III) compounds, probably suggesting a different mechanism of action of such agents. This favorable behavior could be used in order to overcome the resistance effects, by-passing the mitochondrial target and promoting different ways of activity. Taking advantage of proteomics, metabolomics, and experiments on protein metalation, a comprehensive study of structure/activity relationship could suggest specific chemical modifications of the gold-complexes structure that translate to improved biological effects. These findings could also give some important insights on the pharmacodynamics of gold compounds, to predict the eventual off-target action which is commonly responsible for several side effects related to chemotherapeutic treatment. Another strategy to improve efficacy and selectivity of gold complexes is the conjugation to biovectors to deliver the gold-based drug more specifically to the tumors. Gold conjugates to antibodies, aptamers, hormones and vitamins have shown promising results.
The aim of this Research Topic is to disseminate the most recent advances and novel research trends in the synthesis and applications of gold-based drugs. Areas to be covered may include:
- Design and synthesis of new gold complexes including vector-drug conjugates, as well as new insights into their mode-of-action
- Studies of the involved and/or modified pathways after drug administration
- Metabolomics, proteomics and transcriptomics studies related to the gold-based drugs treatment
- Biodistribution and pharmacodynamics studies with hyphenated high-throughput techniques
- New advances for the use of gold compounds in infective diseases (e.g. Amebiasis, Toxoplasmosis, Staphylococcus Aureus infections, etc.)
Moreover, manuscripts concerning similar or strongly related topics are also encouraged. Original Research, Review, Mini-Review, and Perspective articles are all welcome.
Despite the conspicuous number of published papers, the mechanism of action of auranofin (AF) is not fully understood. To date, it is commonly accepted that AF causes a dose-dependent inhibition on DNA, RNA, and protein synthesis at cytotoxic concentrations. However, it is known that only 1–10% of metallodrugs (e.g. cisplatin) accumulated in the cell can reach nuclear DNA. This fact is thought to be strictly correlated with the well-known chemotherapeutic side effects, as the remaining cytotoxic agent probably diffuses in the organism and produces systemic toxicity. In this view, proteins have attracted increasing interest as probable “alternative targets”. Indeed, the activity of AF also relies on inhibiting cell proliferation by induction of apoptotic cell death, which inhibits mitochondrial and cytosolic thioredoxin reductase and leads to oxidative stress.
Several studies have already highlighted the importance of gold compounds, either Au(I) or Au(III), as a promising class of cytotoxic agents with the potential of becoming effective anticancer or anti-infective candidates. Despite their pharmacological potential, the modes of action of these compounds are still largely unknown and a matter of intense research and debate. In the case of Au(I) compounds, mitochondria and pathways of oxidative phosphorylation are seen as the primary intracellular targets. Moreover, inhibition of the selenoenzyme thioredoxin reductase seems to be a common mechanistic trait to explain the action of these compounds, leading to apoptosis through activation of a mitochondrial pathway.
Nonetheless, the treatment with Au(I) complexes can led to some acquired chemoresistance associated with a low level of cross-resistance to the Au(III) compounds, probably suggesting a different mechanism of action of such agents. This favorable behavior could be used in order to overcome the resistance effects, by-passing the mitochondrial target and promoting different ways of activity. Taking advantage of proteomics, metabolomics, and experiments on protein metalation, a comprehensive study of structure/activity relationship could suggest specific chemical modifications of the gold-complexes structure that translate to improved biological effects. These findings could also give some important insights on the pharmacodynamics of gold compounds, to predict the eventual off-target action which is commonly responsible for several side effects related to chemotherapeutic treatment. Another strategy to improve efficacy and selectivity of gold complexes is the conjugation to biovectors to deliver the gold-based drug more specifically to the tumors. Gold conjugates to antibodies, aptamers, hormones and vitamins have shown promising results.
The aim of this Research Topic is to disseminate the most recent advances and novel research trends in the synthesis and applications of gold-based drugs. Areas to be covered may include:
- Design and synthesis of new gold complexes including vector-drug conjugates, as well as new insights into their mode-of-action
- Studies of the involved and/or modified pathways after drug administration
- Metabolomics, proteomics and transcriptomics studies related to the gold-based drugs treatment
- Biodistribution and pharmacodynamics studies with hyphenated high-throughput techniques
- New advances for the use of gold compounds in infective diseases (e.g. Amebiasis, Toxoplasmosis, Staphylococcus Aureus infections, etc.)
Moreover, manuscripts concerning similar or strongly related topics are also encouraged. Original Research, Review, Mini-Review, and Perspective articles are all welcome.
Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.
