Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 10, Issue 4, 2010

I have been pleased to collect together, at the invitation of the Editor-in-Chief of the Anti-Cancer Agents in Medicinal Chemistry, Professor Michelle Prudhomme, a number of papers from researchers with whose work I am familiar, and in some cases participated in, to contribute to this Special Issue of the Journal. The aims and scope of the special issue of Anti-Cancer Agents in Medicinal Chemistry, entitled “Metal-Containing Drugs and Novel Coordination Complexes in Therapeutic Anticancer Applications” were to present up-to-date information on various aspects of metalcontaining or coordination compounds as anticancer therapeutics and to provide the reader with current design rules and delivery strategies. Our hopes are that this area of research would attract some of the most innovative researchers in the field of medicinal chemistry. The application of inorganic chemistry to medicine is a rapidly developing field, and novel therapeutic and diagnostic metals and metal complexes are now having an impact on medical practice. Much attention has focused on designing new coordination compounds with improved pharmacological properties and a broader range of activity. As evident from this special issue and the rapid progress in this area, one cannot resist an expectation that the anticancer metal-based agents progressively find their way into therapeutic and clinical practice. It is further hoped that the current issue will provide a valuable tool and reference for clinical and laboratory research into this fascinating area of cancer research. In this special issue, the experimented researchers specialized on different aspects related to drug development investigations review the most recent advancements on the topic. The current progress for the development of novel effective metal-containing anticancer drugs has been comprehensively discussed and reviewed. The first paper “Status of bi- and multi-nuclear platinum anticancer drug development”, authored by Jinchao Zhang et al. of Hebei University, Baoding, China, describes the structural types and structure-activity rules of non-classical bi- and multi-nuclear platinum anticancer drugs, and discusses their future potential as anticancer agents. These complexes represent a completely new paradigm for platinum based anticancer candidates, and appear to offer great potential as new anticancer agents. In the second paper, entitled “Latest Insights into the anticancer activity of Gold(III)-Dithiocarbamato complexes”, Dolores Fregona, Q. Ping Dou et al., of the University of Padova, Italy and Wayne State University, Detroit, USA, provide a detailed overview on their research work devoted to the design of gold-based anticancer agents, in particular, some gold(III)-dithiocarbamato derivates showing outstanding in vitro and in vivo antitumor properties and reducing, or even no, systemic and renal toxicity, compared to the reference clinically-established anticancer drug cisplatin. The authors comprehensively summarize the results achieved by the group, thoroughly focusing on the latest indepth mechanistic studies that have recently provided insights into their mechanism of action, thus opening up new prospects for further pharmacological testing and entering clinical trials. The third paper of the issue “A better platinum anticancer compound yet to come?”, by Ulrike Olszewski and Gerhard Hamilton of the Ludwig Boltzmann Cluster of Translational Oncology of Vienna, Austria, focuses on the development of the newest generation of platinumbased drugs, such as satraplatin, picoplatin and the multinuclear platinum complex BBR3464 (triplatin), enumerating the encouraging preclinical in vitro and in vivo results. Authors suggest that limited drug design and in vitro and in vivo scantly predictive preclinical tests led to select drug candidates of limited clinical activity. In addition, among the mechanisms of chemoresistance of platinum drugs in vivo, the authors indicate the insufficient diffusion in tumor tissues as an important limiting step in treatment of solid tumors with platinum compounds. They also underscore the need of more representative tumor models, such as resistant primary cancer cell lines, spheroids and orthotopic xenograft models, as the basis for more powerful predictive preclinical assays with Pt-compounds, as well as of new pharmaceutical formulations and bifunctional complexes thus able to achieve clinical activity even in multidrug-resistant tumors. Next, the authors contribute a paper entitled “Mechanisms of cytotoxicity of anticancer Titanocenes“. In this paper Ulrike Olszewski and Gerhard Hamilton describe the historical development and the current status of titanium based cytostatic drugs as anticancer agents. Using information from the literature and their own investigations with titanocene C including genome-wide gene expression in tumor cell lines in vitro a model of the cellular effects of this drug is developed. This review article puts forth a comprehensive analysis of the preclinical and clinical development of titanium-based coordination complexes in the treatment of cancer. Special emphasis is placed on chronicling the molecular targets of titanocenes to gain further insight into their mechanisms of action....

Cisplatin has become one of the most commonly used compounds for the treatment of a wide spectrum of human malignancies. Unfortunately, cisplatin has several major drawbacks. Driven by the impressive impact of cisplatin on cancer chemotherapy, great efforts have been made to develop new derivatives with improved pharmacological properties. Among the over 30 platinum agents which have entered clinical trials after the onset of clinical studies with cisplatin in the early 1970s, only carboplatin and oxaliplatin have received worldwide approval so far, nedaplatin, lobaplatin and heptaplatin have gained regionally limited approval. It has become quite evident that mere analogues of cisplatin or carboplatin will not probably offer any substantial clinical advantages over the existing drugs. Therefore, people turned to synthesize non-classical platinum anticancer drugs which were capable of forming a different range of DNA adducts which could display a different spectrum of anticancer activity compared to cisplatin. This review will summarize the structural types and structure-activity rules of non-classical bi- and multi-nuclear platinum anticancer drugs, and discuss their future potential as anticancer agents.

In this review paper we aim at giving a detailed overview on our research work devoted to the design of gold-based anticancer agents. In particular, during the last decade, we have been developing some gold(III)-dithiocarbamato derivates showing outstanding in vitro and in vivo antitumor properties and reduced, or even no, systemic and renal toxicity, compared to the reference clinically-established anticancer drug cisplatin. Starting from the rationale behind our investigations, we here summarize the results achieved so far, focusing on the latest in-depth mechanistic studies that have recently provided insights into their mechanism of action, thus opening up new prospects for further pharmacological testing and, hopefully, to enter clinical trials.

In attempts to overcome the drawbacks of cisplatin - severe toxicity, drug resistance and poor oral bioavailability - the development of platinum-based drugs has progressed from carboplatin and oxaliplatin to the newest generation of drugs, such as satraplatin, picoplatin and the multinuclear platinum complex BBR3464 (triplatin). Despite encouraging preclinical in vitro and in vivo results, outcomes of clinical trials of these coordination complexes remained below expectations. Biased rationale underlying the drug design along with in vitro and in vivo preclinical tests with inadequate predictive power seem to have eventually resulted in the selection of drug candidates of limited clinical activity. The nature of the active species generated in vivo, uptake, efflux, intracellular trafficking and detailed mechanisms involved in chemoresistance of platinum drugs in vivo are topics that need further investigation to provide clues for the rational formulation of new drugs. Insufficient diffusion in tumor tissues is likely to constitute an important limiting step in the treatment of solid tumors with platinum compounds. Preclinical assays with improved predictive power for the clinical outcome of the compounds should be based on more representative tumor models, such as resistant primary cancer cell lines, spheroids and orthotopic xenograft models, respectively. Finally, use of new pharmaceutical formulations and bifunctional complexes, as well as their selection by decisive preclinical tests, are expected to result in the generation of platinum-based anticancer drugs with the potential to achieve clinical activity even in multidrug-resistant tumors.

The organometallic compound titanocene (bis(cyclopentadienyl)titanium(IV) dichloride) showed promising preclinical anticancer activity in generally resistant tumors in vitro and in vivo but failed in clinical trials. A broad range of analogs with modified cyclopentadienyl ligands conferring increased stability and higher cytotoxicity were developed. Titanium was found to accumulate in the nucleus and inhibit DNA replication and transcription. The active species causing irreversible damage and exact mechanisms of action resulting in cell cycle arrest and apoptosis have not been identified to date. Our group investigated changes in global gene expression of NCI-H526 small cell lung cancer cells in response to the novel analog titanocene C (bis-N,N-dimethylamino-2-(N-methylpyrrolyl) methyl cyclopentadienyl titanium (IV)). Differences observed in transcript levels indicated downregulation of DNA unwinding by topoisomerases I and IIα and activation of responses to DNA damage and cellular stress, as well as shutdown of energy metabolism and, finally, apoptosis. Besides direct interaction of Ti2+ with DNA, induction of the MT1 family of metallothionein genes and downregulation of cellular Zn2+ uptake in response to titanocene C pointed to disturbed Zn2+ homeostasis, which triggers cell cycle arrest and apoptosis due to defective transcription factors and metalloenzymes. In particular, histone H4 genes dependent on Zn2+-containing transcription factors H4TF-1/2 were specifically downregulated, and accumulation of defective metalloproteins in the endoplasmatic reticulum seemed to activate unfolded protein response. In conclusion, according to these results, we propose a model of titanocene-induced cytotoxicity, comprising direct DNA damage and perturbation of Zn2+ homeostasis with impairment of the functions of cellular metalloproteome.

Ruthenium compounds have been actively studied as metallodrugs for cancer therapy. Representatives of ruthenium-based antitumor drugs are the classes of ruthenium(III)-chlorido-(N-ligand) complexes, including the drugs namely NAMI-A and KP1019 in clinical trials, and ruthenium(II)-arene organometallics, with some compounds currently undergoing advanced preclinical testing. An alternative approach for tumor-inhibiting metallodrugs is the coordination of metal ions to organic pharmaceuticals. The combination of antitumor-active ruthenium ion with biologically-active pro-ligands in single compounds can result in the enhancement of activity, for example through synergistic effects. In the present article, some developments in the ruthenium-based antitumor drugs field are briefly highlighted and recent studies on mixed diruthenium-organic drugs as metallopharmaceuticals in cancer therapy are described. Novel organic pharmaceuticals-containing diruthenium(II,III) complexes have shown promising antitumor activity for C6 rat glioma - a model for glioblastoma multiforme (GBA).

Since the discovery of cisplatin and its introduction in the clinics, metal compounds have been intensely investigated in view of their possible application in cancer therapy. In this frame, a deeper understanding of their mode of action, still rather obscure, might turn crucial for the design and the obtainment of new and better anticancer agents. Due to the extreme complexity of the biological systems, it is now widely accepted that innovative and information-rich methods are absolutely needed to afford such a goal. Recently, both proteomic and metallomic strategies were successfully implemented for the elucidation of specific mechanistic features of anticancer metallodrugs within an innovative “Systems Biology” perspective. Particular attention was paid to the following issues: i) proteomic studies of the molecular basis of platinum resistance; ii) proteomic analysis of cellular responses to cytotoxic metallodrugs; iii) metallomic studies of the transformation and fate of metallodrugs in cellular systems. Notably, those pioneering studies, that are reviewed here, allowed a significant progress in the understanding of the molecular mechanisms of metal based drugs at the cellular level. A further extension of those studies and a closer integration of proteomic and metallomic strategies and technologies might realistically lead to rapid and significant advancements in the mechanistic knowledge of anticancer metallodrugs.

Hepatocellular carcinoma (HCC) happens to be one of the most lethal cancers in the world. Even though most cases occur in the developing world, reported cases in Western Europe as well as North America are on a steep rise. Human HCC etiology includes chronic liver disease, viral hepatitis, alcoholism, iron overload as well as dietary carcinogens such as aflatoxins and nitrosoamines. Surgical resection as well as liver transplants, which are currently used to treat HCC, is mostly ineffective. Consequently, there exists a decisive requirement to explore possible alternative chemopreventive and therapeutic strategies for HCC. Both oxidative stress and inflammatory mechanisms have been implicated in the pathophysiology of HCC. The use of dietary antioxidants and micronutrients has been proposed as an effective means for successful management of human HCC. Trace elements such as vanadium and selenium are involved in several major metabolic pathways as well as antioxidant defense systems. Selenium has been shown to be involved in the prevention of numerous chronic illnesses such as several specific cancers and neurodegenerative diseases. This review examines the potential role of selenium in the prevention and treatment of HCC. The in vivo and in vitro effects of selenium and the mechanisms involved in preclinical models of liver cancer are critically reviewed in this article. The chemopreventive and therapeutic effects of selenium are reviewed especially in relation to its antioxidant property. Future directions and potential challenges involved in the advance of selenium use in the prevention and treatment of liver cancer are also discussed.

In the last few years boron (B) compounds became increasingly frequent in the chemotherapy of some forms of cancer with high malignancy and of inoperable cancers. As more B-based therapy chemicals are developed it is necessary to review the correlation between B and the incidence of different forms of cancer, the biochemical and molecular mechanisms influenced by B and to explore the relevance of B in the chemoprevention of cancer. This minireview analyzes dietary and therapeuptic principles based on the chemistry of B compounds. We summarize studies correlating B-rich diets or B-rich environments with regional risks of specific forms of cancers, and studies about the utilization of natural and synthetic B-containing compounds as anticancer agents. We review mechanisms where B-containing compounds interfere with the physiology and reproduction of cancer cells. Types of cancers most frequently impacted by B-containing compounds include prostate, breast, cervical and lung cancer. Mechanisms involving B activity on cancer cells are based on the inhibition of a variety of enzymatic activities, including serine proteases, NAD-dehydrogenases, mRNA splicing and cell division, but also receptor binding mimicry, and the induction of apoptosis. Boron-enriched diets resulted in significant decrease in the risk for prostate and cervical cancer, and decrease in lung cancer in smoking women. Boron-based compounds show promising effects for the chemotheraphy of specific forms of cancer, but due to specific benefits should also be included in cancer chemopreventive strategies.