Titanium Tackles the Endoplasmic Reticulum: A First Genomic Study on a Titanium Anticancer Metallodrug (original) (raw)
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Coordination Chemistry Reviews, 2018
Platinum drugs are extensively used in the clinic to treat cancer, often leading to a palliative response rather than a cure. While DNA is considered to be the primary target of platinum drugs, there is no clear relationship between cellular platinum accumulation, DNA platination and Pt-DNA adduct removal, and herein we describe new mechanistic insights of platinum drugs related to the hallmarks of cancer and how they interfere with the tumour microenvironment. We then proceed to describe the properties of other metal drugs, including both non-targeted compounds that do not significantly interact with DNA and targeted compounds that interfere more selectively with specific pathways responsible for tumour growth and invasion. Our analysis of the cancer biology and the selected drugs allows us to propose possible routes for future drug development based on metal scaffolds.
Proteomic and Metallomic Strategies for Understanding the Mode of Action of Anticancer Metallodrugs
Anti-Cancer Agents in Medicinal Chemistry, 2010
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 metallo...
Inorganic Chemistry, 2011
Metal-based drugs are nowadays among the most effective therapeutic agents for the treatment of cancer, with cisplatin, carboplatin, and oxaliplatin being widely used in clinics. 1 However, their effectiveness is still hindered by clinical problems, including acquired or intrinsic resistance, a limited spectrum of activity, and high toxicity leading to side effects. 2 Therefore, anticancer platinum compounds continue to be designed and synthesized through several different approaches in order to improve the therapeutic effects and to overcome the disadvantages of current platinum-based drugs. 3À6 The use of transition metal compounds other than platinum has also attracted attention in metallodrugs' development. 7À9 Among the thousands of inorganic derivatives synthesized and tested so far, only three nonplatinum-based complexes have reached phase II of clinical trials, namely, the organometallic compound titanocene dichloride (Ti(η 5-C 5 H 5) 2 Cl 2) 10 and the Ru-based coordination compounds KP1019 11 and NAMI-A 12 (Chart 1). Recent studies have shown that compounds based on gold are also promising anticancer drugs, and a conspicuous number of gold(III) and gold(I) complexes, with highly different chemical structures, have proven Chart 1. Nonplatinum-Based Anticancer Complexes Having Reached Phase II of Clinical Trials
Molecules
Metal complexes have been used to treat cancer since the discovery of cisplatin and its interaction with DNA in the 1960’s. Facing the resistance mechanisms against platinum salts and their side effects, safer therapeutic approaches have been sought through other metals, including ruthenium. In the early 2000s, Michel Pfeffer and his collaborators started to investigate the biological activity of organo-ruthenium/osmium complexes, demonstrating their ability to interfere with the activity of purified redox enzymes. Then, they discovered that these organo-ruthenium/osmium complexes could act independently of DNA damage and bypass the requirement for the tumor suppressor gene TP53 to induce the endoplasmic reticulum (ER) stress pathway, which is an original cell death pathway. They showed that other types of ruthenium complexes—as well complexes with other metals (osmium, iron, platinum)—can induce this pathway as well. They also demonstrated that ruthenium complexes accumulate in the...
Structural features of antitumor titanium agents and related compounds
Bioinorganic Chemistry and …, 2005
Previous studies established some Ti compounds as having marked activity against tumors of the gastrointestinal tract and lack of side effects common to widely used cytostatic agents. We describe pertinent structural features of known antitumor Ti agents and other potentially active compounds. Particularly noteworthy features are that Ti-O bonds are short and Ti-O-Ti bond angles are large, demonstrating that in these compounds the O binding has high s-character approaching sp hybridization. /'he successful drug development/1/of the antitumor agent cis-diaminodichloroplatinum(II) (cisplatin) 1, generated a search for other active metal compounds and cis-diethoxy-bis(1-phenylbutane-l,3dionato)titanium(IV), [(bzac)2Ti(OEt)2] (budotitane) 2, was the first non-Pt metal antitumor compound that reached clinical trials /2/. The ligand 1-phenylbutane-l,3-dionato bzac benzoylacetonato, is an asymmetric [3-diketone chelator useful tbr establishing one key structural feature tbr activity in budotitane, namely, the existence of two OEt cis leaving groups, which arc analogous to the 2 CI in cisplatin. Another Ti antitumor agent is titanocene dichloride, (Cp)2TiCI2 3, Cp cyclopentadienyl, which possesses 2 CI leaving groups/5/. Among the differences between Ti antitumor drugs and cisplatin is the spectrum of activity, as Ti drugs operate against gastrointestinal tumors whereas Pt drugs do not. On the other hand, P338 and LI210 leukemia are sensitive targets for Pt drugs but not for budotitane/4/. Other differences include a much faster hydrolysis rate of the leaving groups in the former, and the environment where the metal-leaving group bonds cleave: outside the cell for Ti drugs and inside the cell tbr Pt drugs/1/. Titanocenc dichloride shows a larger spectrum of activity compared to budotitane. This is likely due to better solubility in physiological medium and it is currently in phase II clinical tests /5/, whereas the Structural Features of Antitumor Titanium. Agents and Related Compounds development of budotitane is limited by formulation problems /6/. Titanocene dichloride interacts with transferrin, a protein associated with iron transport, and suggests a possible mode of entry into the tumor cell. That is, the protein, with a Ti atom bound to one of its 2 domains/7,8/, could cross the tumor cell wall, which is characterized by greater amount of transferrin receptors than present in normal cells, and allow metal interaction with unknown targets.
Cytotoxicity of a Ti(IV) compound is independent of serum proteins
Proceedings of the National Academy of Sciences, 2012
Titanium(IV) compounds are excellent anticancer drug candidates, but they have yet to find success in clinical applications. A major limitation in developing further compounds has been a general lack of understanding of the mechanism governing their bioactivity. To determine factors necessary for bioactivity, we tested the cytotoxicity of different ligand compounds in conjunction with speciation studies and mass spectrometry bioavailability measurements. These studies demonstrated that the Ti(IV) compound of N, N′-di(o-hydroxybenzyl)ethylenediamine-N,N′-diacetic acid (HBED) is cytotoxic to A549 lung cancer cells, unlike those of citrate and naphthalene-2,3-diolate. Although serum proteins are implicated in the activity of Ti(IV) compounds, we found that these interactions do not play a role in [TiO(HBED)] − activity. Subsequent compound characterization revealed ligand properties necessary for activity. These findings establish the importance of the ligand in the bioactivity of Ti(IV) compounds, provides insights for developing next-generation Ti(IV) anticancer compounds, and reveal [TiO (HBED)] − as a unique candidate anticancer compound. drug delivery | transferrin | albumin | metal-based anticancer compounds
The molecular mechanisms of antimetastatic ruthenium compounds explored through DIGE proteomics
Journal of Inorganic Biochemistry, 2013
DIGE (difference in gel electrophoresis) proteomics is exploited here to gain insight into the molecular mechanisms of two established ruthenium-based antimetastatic agents, namely trans-[tetrachloro (DMSO) (imidazole)ruthenate(III)] (NAMI-A) and [Ru(η 6 -toluene)Cl 2 (PTA)] (RAPTA-T), where PTA is 1,3,5-triaza-7-phosphaadamantane. Following 24 h exposure of A2780/S human ovarian carcinoma cells to pharmacologically relevant concentrations of either ruthenium compound, 2D-DIGE proteomic analysis evidenced only few differentially expressed proteins with respect to controls. Successive mass spectrometry measurements, MALDI-TOF (matrix assisted laser desorption ionization-time of flight) or LC-ESI/MS-MS (liquid chromatographyelectrospray ionization/multi-stage mass spectrometry), allowed identification of most altered protein spots, some of which were associated to perturbations in specific cellular functions. Direct insight into the cellular effects of the investigated metallodrugs is thus achieved. Notably, the patterns of protein alterations induced by NAMI-A and RAPTA-T are quite similar to each other while being deeply different from those of cisplatin. To the best of our knowledge this is the first proteomic study on human cancer cells investigating responses to antimetastatic ruthenium drugs. The key role of new "omic" approaches for deciphering the elusive and complex biochemical mechanisms through which anticancer metallodrugs produce their pharmacological effects is further documented.
Journal of Chemical Biology, 2012
Platinum-based DNA metallointercalators are structurally different from the covalent DNA binders such as cisplatin and its derivatives but have potent in vitro activity in cancer cell lines. However, limited understanding of their molecular mechanisms of cytotoxic action greatly hinders their further development as anticancer agents. In this study, a lead platinum-based metallointercalator, [(5,6dimethyl-1,10-phenanthroline) (1S,2S-diaminocyclohexane) platinum(II)] 2+ (56MESS) was found to be 163-fold more active than cisplatin in a cisplatin-resistant cancer cell line. By using transcriptomics in a eukaryotic model organism, yeast Saccharomyces cerevisiae, we identified 93 genes that changed their expressions significantly upon exposure of 56MESS in comparison to untreated controls (p≤0.05). Bioinformatic analysis of these genes demonstrated that iron and copper metabolism, sulfur-containing amino acids and stress response were involved in the cytotoxicity of 56MESS. Follow-up experiments showed that the iron and copper concentrations were much lower in 56MESS-treated cells compared to controls as measured by inductively coupled plasma optical emission spectrometry. Deletion mutants of the key genes in the iron and copper metabolism pathway and glutathione synthesis were sensitive to 56MESS. Taken together, the study demonstrated that the cytotoxic action of 56MESS is mediated by its ability to disrupt iron and copper metabolism, suppress the biosynthesis of sulfur-containing amino acids and attenuate cellular defence capacity. As these mechanisms are in clear contrast to the DNA binding mechanism for cisplatin and its derivative, 56MESS may be able to overcome cisplatinresistant cancers. These findings have provided basis to further develop the platinum-based metallointercalators as anticancer agents.