Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 11, Issue 10, 2011

This special issue is focused in the applications of gold derivatives as anti-cancer agents, a research area that is in growing development in the recent years. Gold complexes were already known as rheumatoid arthritis agents for a long time, but their anti-cancer capabilities are much less explored. Interestingly, this emerging research area uses very top techniques such as proteomics, fluorescence microscopy, nanochemistry, luminescence… This thematic issue presents different contributions (as review articles) that include a wide range of different methodologies that work straightforward to this goal. It also shows a sample of the very different kind of compounds (from mononuclear complexes to nanoparticules) with positive effect in this research. Moreover, the mechanistic studies and the biological strategies followed by these drugs is also analyzed in some of the manuscripts. Thus, gold(I) drugs represent a valuable new tool for medicine applications due to the wide range of properties exhibited by their derivatives and also, it is important to note that they could be modulated in a particular way by the change or slight modifications of the coordinated ligands and/or in the structure of the nanoparticles. All of this could be found in this Special Issue entitled “Gold Derivatives as Anticancer Agents”. Phosphine-Gold(I) Compounds As Anticancer Agents: General Description And Mechanisms of Action. Joao Carlos Lima and Laura Rodriguez The present paper is an overview of the different gold-phosphine derivatives used as anticancer agents and reported in the literature until now. Their mechanism of action seems to be clearly different that the used by platinum drugs (DNA intercalating processes) and recent studies point to be related to the inhibition of Trx reductase. The use of luminescence techniques in these studies is scarcely found and is also here explored. Protein Targets for Anticancer Gold Compounds: Mechanistic Inferences. Chiara Gabbiani and Luigi Messori Gold compounds, either gold(III) or gold(I), were recently described and characterised that manifested remarkable cytotoxic properties in vitro against cultured cancer cells. In this paper, the molecular mechanisms through which gold compounds exert their biological effects are shown and, in particular, gold interactions with a variety of protein targets. The state of the art of this research area and the perspectives for future studies are herein critically analysed and discussed....

Gold complexes have been explored as metallodrugs with great potential applications as antitumoral agents. In particular, gold-phosphine derivatives seemed quite promising since the use of the antiarthritic auranofin drug (thiolate-Au-PEt3 complex) presented also biological activity against different cancer cells. So, different auranofin analogues have been explored within this context and for this reason, the main number of phosphine-gold complexes developed with this goal contain thiolate ligands. Other complexes have been also studied such as tetrahedral bis(phosphine)gold(I) and phosphine-gold-halides. Very recently, phosphine-gold-alkynyl complexes have also shown very interesting biological activities although few reports are published related to them. Their mechanism of action seems to be clearly different that the used by platinum drugs (DNA intercalating processes) and recent studies point to be related to the inhibition of Trx reductase. Cellular uptake and biodistribution studies are well reported in the original works but the use of luminescence techniques is relatively less explored. For this, the use of these techniques is also specifically reported in this review.

Gold compounds form an interesting class of antiproliferative agents of potential pharmacological use in cancer treatment. Indeed, a number of gold compounds, either gold(III) or gold(I), were recently described and characterised that manifested remarkable cytotoxic properties in vitro against cultured cancer cells; for some of them encouraging in vivo results were also reported toward a few relevant animal models of cancer. The molecular mechanisms through which gold compounds exert their biological effects are still largely unknown and the subject of intense investigations. Recent studies point out that the modes of action of cytotoxic gold compounds are essentially DNA-independent and cisplatin-unrelated, relying -most likely- on gold interactions with a variety of protein targets. Notably, a few cellular proteins playing relevant functional roles were proposed to represent effective targets for cytotoxic gold compounds but these hypotheses need adequate validation. The state of the art of this research area and the perspectives for future studies are herein critically analysed and discussed.

Since the introduction of the monomeric orally bioavailable anti-arthritic gold compound auranofin in 1985, and the success of the platinum-based anti-cancer drugs, there has been a great deal of interest in the use of gold compounds for cancer therapy. However this early promise has not materialized into an approved drug in spite of extensive and innovative efforts in gold chemistry. Therefore, in the light of this lack of success, the strategies for the biological evaluation of potential gold-based anti-cancer drugs are discussed. It is proposed that the biological testing strategy should be multi-faceted incorporating an understanding of the molecular properties of the compounds under investigation related to their behaviour in a biological environment, an evaluation of their comparative in vitro potency against tumor cells, ascertaining the biochemical mechanism of action and target identification to aid in medicinal chemistry design, evaluation of in vivo activity in relevant tumor models, and an understanding of their toxicological and pharmacokinetic properties. This strategy will be exemplified with work on Au(III) cyclometallated complexes in which an integrated approach to the search for new metal-based anticancer drugs was adopted, incorporating in vitro screening, in vivo human tumor xenograft models, and mechanistic studies. The importance of mechanistic studies which have led to the identification of new molecular targets for gold drugs, and in vivo evaluation are emphasized.

Well-designed photothermal nanostructures have attracted many scientists pursuing a better means to accurately diagnose cancer and assess the efficacy of treatment. Recently, gold-based nanostructures (nanoshells, nanorods and nanocages) have enabled photothermal ablation of cancer cells with near-infrared (NIR) light without damaging normal human tissues and in particular, animal studies and early clinical testing showed the great promise for these materials. In this review article, we first discuss the mechanism of the cellular death signaling by thermal stress and introduce the intrinsic properties of gold nanostructures as photothermal agent for cancer treatment. Then the overview follows for evolving researches for the synthesis of various types of gold nanostructures and for their biomedical applications. Finally we introduce the optimized therapeutic strategies involving nanoparticle surface modification and laser operation method for an enhanced accumulation of gold nanostructures to the target cancer as well as for an effective cancer cell ablation.

Over the last few decades, the study of nanotechnology has grown exponentially. Nanotechnology bridges science, engineering and technology; it continues to expand in definition as well as practice. One sub-set of nanotechnology is bionanotechnology, this will be the focus of this review. Currently, bionanotechnology is being studied and exploited for utility within medicinal imaging, diagnosis and therapy in regard to cancer. Cancer is a world-wide health problem and the implication rate as well as the death rate increase year to year. However promising work is being done with gold nanoparticles for detection, diagnosis and targeted drug delivery therapy. Gold nanoparticles can be synthesized in various shapes and sizes, which directly correlates to the color; they can also be manipulated to carry various antibody, protein, plasmid, DNA or small molecule drug. Herein we summarize some of the very influential research being done in the field of Cancer Nanotechnology with an emphasis on gold nanoparticles.

CORAL software (http://www.insilico.eu/coral/) has been used for modeling of carcinogenicity (logTD50) of 401 compounds, and anticancer activity (-logIC50) of 100 compounds, on the basis of quantitative structure - activity relationships (QSAR). The simplified molecular input line entry system (SMILES) was used for the representation of the molecular structures. A new additional global invariant of the molecular structure was tested. This is an indicator of the presence of pairs of chemical elements (F, Cl, Br, N, O, S, and P). Three random splits into sub-training, calibration, and test set were examined. Molecular features (calculated with SMILES and statistically significant), which increase the anticancer activity have been identified: their presence in the molecular structure could be helpful criterion in the search for new anticancer agents.

Tumor growth depends upon access to host blood vessels. Many steps in tumor angiogenesis have been defined including tumor cell hypoxia, tumor cell secretion of pro-angiogenic growth factors, receptor activation on host endothelium and stroma, and establishment of new blood vessels feeding the tumor mass. Inhibitors for some of these steps have been synthesized and tested clinically. While modest improvements in response, progression-free survival and overall survival have been observed in metastatic colorectal carcinoma, non-small cell lung carcinoma, breast carcinoma, renal cell carcinoma, and glioblastoma, almost all patients ultimately relapse and die from metastatic disease. Explanations for the limited effects of anti-angiogenesis therapy include lack of activity on all the parallel angiogenic pathways, non-specific toxicities of some of the agents, induction of a pro-metastatic phenotype by the enhanced hypoxia from therapy, and lack of effect on already established tumor blood vessels. One solution is to directly attack the tumor vasculature rather than inhibit tumor vessel formation. The flavonoid ASA404 and the tubulin-binder combretastatin A-4 phosphate directly damage tumor endothelium by different mechanisms. Both compounds have shown minimal single agent disease activity and produce cardiac ischemia in clinical trials. Recently, ligand-directed vascular disrupting agents have been synthesized and tested. A promising member of this class of therapeutics targets the tumor endothelial marker-8 (TEM8). Anti-TEM8 antibody drug conjugate may facilitate selective destruction of tumor blood vessels yielding enhanced anti-cancer efficacy and reduced normal tissue toxicities. Advances in this field are described which should lead to clinical studies of TEM8 targeted cancer therapeutics.

AKT (or protein kinase B) and focal adhesion kinase (FAK) are two important kinases that regulate various cellular functions. Each is overexpressed and/or aberrantly activated in diverse cancers. Several small molecular inhibitors targeting either AKT or FAK are in development or in clinical trials. It is well established that FAK is an upstream regulator of AKT signaling pathway in various cancer cell lines and in xenograft tumor models. However, very recent reports from our laboratory and others demonstrate that AKT can also directly regulate FAK through direct association and serine phosphorylation. This indicates that AKT and FAK may be dual therapeutic targets for pharmacologic intervention in the treatment of primary and metastatic cancer. FAK-AKT interaction is particularly critical for metastatic adhesion. We review recent developments in AKT and FAK signaling in cancer with the particular emphasis on the novel signaling pathways in which FAK is downstream of AKT. We also provide an update on inhibitors targeting AKT or FAK currently in clinical trials.