In this work, the mechanism underlying the anticancer activity of a photoactivatable Ir(III) compound of the type [Ir(C^N)2(dppz)][PF6] where C^N = 1-methyl-2-(2'-thienyl)benzimidazole (complex 1) was investigated. Complex 1 photoactivated by visible light shows potent activity against highly aggressive and poorly treatable Rhabdomyosarcoma (RD) cells, the most frequent soft tissue sarcomas of children. This remarkable activity of 1 was observed not only in RD cells cultured in 2D monolayers but, more importantly, also in 3D spheroids, which resemble in many aspects solid tumors and serve as a promising model to mimic the in vivo situation. Importantly, photoactivated 1 kills not only differentiated RD cells but also even more effectively cancer stem cells (CSCs) of RD. One of the factors responsible for the activity of irradiated 1 in RD CSCs is its ability to produce ROS in these cells more effectively than in differentiated RD cells. Moreover, photoactivated 1 caused in RD differentiated cells and CSCs a significant decrease of mitochondrial membrane potential and promotes opening mitochondrial permeability transition pores in these cells, a mechanism that has never been demonstrated for any other metal-based anticancer complex. The results of this work give evidence that 1 has a potential for further evaluation using in vivo models as a promising chemotherapeutic agent for photodynamic therapy of hardly treatable human Rhabdomyosarcoma, particularly for its activity in both stem and differentiated cancer cells.

• Klíčová slova
• Antitumor activity, Cancer stem cells, Mitochondria, Phototoxic iridium complex, Rhabdomyosarcoma cells,
• MeSH
• dítě MeSH
• iridium farmakologie   MeSH
• komplexní sloučeniny * farmakologie   MeSH
• lidé MeSH
• mitochondrie MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky MeSH
• protinádorové látky * farmakologie   MeSH
• rhabdomyosarkom * farmakoterapie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• iridium MeSH
• komplexní sloučeniny * MeSH
• protinádorové látky * MeSH

Mitochondria are essential cellular organelles, controlling multiple signalling pathways critical for cell survival and cell death. Increasing evidence suggests that mitochondrial metabolism and functions are indispensable in tumorigenesis and cancer progression, rendering mitochondria and mitochondrial functions as plausible targets for anti-cancer therapeutics. In this review, we summarised the major strategies of selective targeting of mitochondria and their functions to combat cancer, including targeting mitochondrial metabolism, the electron transport chain and tricarboxylic acid cycle, mitochondrial redox signalling pathways, and ROS homeostasis. We highlight that delivering anti-cancer drugs into mitochondria exhibits enormous potential for future cancer therapeutic strategies, with a great advantage of potentially overcoming drug resistance. Mitocans, exemplified by mitochondrially targeted vitamin E succinate and tamoxifen (MitoTam), selectively target cancer cell mitochondria and efficiently kill multiple types of cancer cells by disrupting mitochondrial function, with MitoTam currently undergoing a clinical trial.

• Klíčová slova
• anti-cancer strategy, drug delivery, mitocans, mitochondrial targeting,
• MeSH
• chemorezistence účinky léků   MeSH
• cílená molekulární terapie MeSH
• citrátový cyklus účinky léků   MeSH
• elektronový transportní řetězec účinky léků   metabolismus   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• nádory farmakoterapie   metabolismus   MeSH
• oxidace-redukce účinky léků   MeSH
• progrese nemoci MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• signální transdukce účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• elektronový transportní řetězec MeSH
• protinádorové látky MeSH

This review deals with the antigene strategy whereby an oligonucleotide binds to the major or minor groove of double helical DNA where it forms a local triple helix. Preoccupation of this article is triplex-forming oligonucleotides (TFO). These are short, synthetic single-stranded DNAs that recognize polypurine:polypyrimidine regions in double stranded DNA in a sequence-specific manner and form triplex. Therefore, the mechanisms for DNA recognition by triple helix formation are discussed, together with main characteristics of TFO and also major obstacles that remain to be overcome are highlighted. TFOs can selectively inhibit gene expression at the transcriptional level or repair genetic defect by direct genome modification in human cells. These qualities makes TFO potentially powerful therapeutic tool for gene repair and/or expression regulation.

• MeSH
• DNA * chemie   metabolismus   MeSH
• genový targeting * MeSH
• konformace nukleové kyseliny MeSH
• minoxidil MeSH
• nylony chemie   metabolismus   MeSH
• oligoribonukleotidy * chemie   metabolismus   MeSH
• pyrimidiny chemie   metabolismus   MeSH
• regulace genové exprese * MeSH
• vazba proteinů MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• DNA * MeSH
• minoxidil MeSH
• nylony MeSH
• oligoribonukleotidy * MeSH
• pyrimidiny MeSH
• triplex DNA MeSH Prohlížeč

BACKGROUND: Nanoparticle-based systems are promising for the development of imaging and therapeutic agents. The main advantage of nanoparticles over traditional systems lies in the possibility of loading multiple functionalities onto a single molecule, which are useful for therapeutic and/or diagnostic purposes. These functionalities include targeting moieties which are able to recognize receptors overexpressed by specific cells and tissues. However, targeted delivery of nanoparticles requires an accurate system design. We present here a rationally designed, genetically engineered, and chemically modified protein-based nanoplatform for cell/tissue-specific targeting. METHODS: Our nanoparticle constructs were based on the heavy chain of the human protein ferritin (HFt), a highly symmetrical assembly of 24 subunits enclosing a hollow cavity. HFt-based nanoparticles were produced using both genetic engineering and chemical functionalization methods to impart several functionalities, ie, the α-melanocyte-stimulating hormone peptide as a melanoma-targeting moiety, stabilizing and HFt-masking polyethylene glycol molecules, rhodamine fluorophores, and magnetic resonance imaging agents. The constructs produced were extensively characterized by a number of physicochemical techniques, and assayed for selective melanoma-targeting in vitro and in vivo. RESULTS: Our HFt-based nanoparticle constructs functionalized with the α-melanocyte-stimulating hormone peptide moiety and polyethylene glycol molecules were specifically taken up by melanoma cells but not by other cancer cell types in vitro. Moreover, experiments in melanoma-bearing mice indicate that these constructs have an excellent tumor-targeting profile and a long circulation time in vivo. CONCLUSION: By masking human HFt with polyethylene glycol and targeting it with an α-melanocyte-stimulating hormone peptide, we developed an HFt-based melanoma-targeting nanoplatform for application in melanoma diagnosis and treatment. These results could be of general interest, because the same strategy can be exploited to develop ad hoc nanoplatforms for specific delivery towards any cell/tissue type for which a suitable targeting moiety is available.

• Klíčová slova
• cancer-targeting, ferritin, melanoma, multifunctional nanoparticles, nanoplatform,
• MeSH
• alfa-MSH chemie   MeSH
• apoferritiny chemie   MeSH
• buňky HT-29 MeSH
• fluorescenční barviva chemie   MeSH
• konfokální mikroskopie MeSH
• lékové transportní systémy MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• magnetické nanočástice * chemie   ultrastruktura   MeSH
• melanom experimentální diagnóza   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nanomedicína MeSH
• nanotechnologie MeSH
• polyethylenglykoly chemie   MeSH
• rekombinantní proteiny chemie   MeSH
• stabilita proteinů MeSH
• transmisní elektronová mikroskopie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• alfa-MSH MeSH
• apoferritiny MeSH
• fluorescenční barviva MeSH
• magnetické nanočástice * MeSH
• polyethylenglykoly MeSH
• rekombinantní proteiny MeSH

Cyclin-dependent kinases (CDKs) are an important and emerging class of drug targets for which many small-molecule inhibitors have been developed. However, there is often insufficient data available on the selectivity of CDK inhibitors (CDKi) to attribute the effects on the presumed target CDK to these inhibitors. Here, we highlight discrepancies between the kinase selectivity of CDKi and the phenotype exhibited; we evaluated 31 CDKi (claimed to target CDK1-4) for activity toward CDKs 1, 2, 4, 5, 7, 9 and for effects on the cell cycle. Our results suggest that most CDKi should be reclassified as pan-selective and should not be used as a tool. In addition, some compounds did not even inhibit CDKs as their primary cellular targets; for example, NU6140 showed potent inhibition of Aurora kinases. We also established an online database of commercially available CDKi for critical evaluation of their utility as molecular probes. Our results should help researchers select the most relevant chemical tools for their specific applications.

• MeSH
• buněčný cyklus účinky léků   MeSH
• chinoliny farmakologie   MeSH
• cyklin-dependentní kinasy antagonisté a inhibitory   MeSH
• HCT116 buňky MeSH
• inhibitory proteinkinas farmakologie   MeSH
• lidé MeSH
• thiazoly farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chinoliny MeSH
• cyklin-dependentní kinasy MeSH
• inhibitory proteinkinas MeSH
• RO 3306 MeSH Prohlížeč
• thiazoly MeSH

SIGNIFICANCE: Mitochondria are emerging as highly intriguing organelles showing promise but that are yet to be fully exploited as targets for anticancer drugs. RECENT ADVANCES: A group of compounds that induce mitochondrial destabilization, thereby affecting the physiology of cancer cells, has been defined and termed 'mitocans.' Based on their mode of action of targeting in and around mitochondria, we have placed these agents into several groups including hexokinase inhibitors, compounds targeting Bcl-2 family proteins, thiol redox inhibitors, VDAC/ANT targeting drugs, electron transport chain-targeting drugs, lipophilic cations targeting the inner membrane, agents affecting the tricarboxylic acid cycle, drugs targeting mtDNA, and agents targeting other presently unknown sites. CRITICAL ISSUES: Mitocans have a potential to prove highly efficient in suppressing various malignant diseases in a selective manner. They include compounds that are currently in clinical trial and offer substantial promise to become clinically applied drugs. Here we update and redefine the individual classes of mitocans, providing examples of the various members of these groups with a particular focus on agents targeting the electron transport chain, and indicate their potential application in clinical practice. FUTURE DIRECTIONS: Even though reactive oxygen species induction is important for the anticancer activity of many mitocans, the precise sequence of events preceding and following this pivotal event are not yet fully clarified, and warrant further investigation. This is imperative for effective deployment of these compounds in the clinic.

• MeSH
• cílená molekulární terapie MeSH
• elektronový transportní řetězec metabolismus   MeSH
• lidé MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• nádory farmakoterapie   metabolismus   MeSH
• protinádorové látky klasifikace   farmakologie   MeSH
• transport elektronů účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• elektronový transportní řetězec MeSH
• protinádorové látky MeSH

Glutamate carboxypeptidase II (GCPII) is a membrane protease overexpressed by prostate cancer cells and detected in the neovasculature of most solid tumors. Targeting GCPII with inhibitor-bearing nanoparticles can enable recognition, imaging, and delivery of treatments to cancer cells. Compared to methods based on antibodies and other large biomolecules, inhibitor-mediated targeting benefits from the low molecular weight of the inhibitor molecules, which are typically stable, easy-to-handle, and able to bind the enzyme with very high affinity. Although GCPII is established as a molecular target, comparing previously reported results is difficult due to the different methodological approaches used. In this work, we investigate the robustness and limitations of GCPII targeting with a diverse range of inhibitor-bearing nanoparticles (various structures, sizes, bionanointerfaces, conjugation chemistry, and surface densities of attached inhibitors). Polymer-coated nanodiamonds, virus-like particles based on bacteriophage Qβ and mouse polyomavirus, and polymeric poly(HPMA) nanoparticles with inhibitors attached by different means were synthesized and characterized. We evaluated their ability to bind GCPII and interact with cancer cells using surface plasmon resonance, inhibition assay, flow cytometry, and confocal microscopy. Regardless of the diversity of the investigated nanosystems, they all strongly interact with GCPII (most with low picomolar Ki values) and effectively target GCPII-expressing cells. The robustness of this approach was limited only by the quality of the nanoparticle bionanointerface, which must be properly designed by adding a sufficient density of hydrophilic protective polymers. We conclude that the targeting of cancer cells overexpressing GCPII is a viable approach transferable to a broad diversity of nanosystems.

• Klíčová slova
• GCPII, PSMA, cell, click chemistry, inhibitor, multivalent binding, nanodiamond, nonspecific interaction, polymer, targeting, virus-like particle,
• MeSH
• antigeny povrchové metabolismus   MeSH
• click chemie MeSH
• farmaceutická chemie MeSH
• glutamátkarboxypeptidasa II antagonisté a inhibitory   metabolismus   MeSH
• hydrofobní a hydrofilní interakce MeSH
• inhibitory enzymů aplikace a dávkování   MeSH
• lidé MeSH
• ligandy MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   patologie   MeSH
• nanokonjugáty chemie   MeSH
• protinádorové látky aplikace a dávkování   MeSH
• rekombinantní proteiny metabolismus   MeSH
• thiazolidiny chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 2-mercaptothiazoline MeSH Prohlížeč
• antigeny povrchové MeSH
• FOLH1 protein, human MeSH Prohlížeč
• glutamátkarboxypeptidasa II MeSH
• inhibitory enzymů MeSH
• ligandy MeSH
• nanokonjugáty MeSH
• protinádorové látky MeSH
• rekombinantní proteiny MeSH
• thiazolidiny MeSH

Fibroblast activation protein (FAP, seprase) is a serine protease with post-proline dipeptidyl peptidase and endopeptidase enzymatic activity. FAP is upregulated in several tumor types, while its expression in healthy adult tissues is scarce. FAP molecule itself and FAP+ stromal cells play an important although probably context-dependent and tumor type-specific pathogenetic role in tumor progression. We provide an overview of FAP expression under both physiological and pathological conditions with focus on human malignancies. We also review and critically analyze the results of studies which used various strategies for the therapeutic targeting of FAP including the use of low molecular weight inhibitors, FAP activated prodrugs, anti-FAP antibodies and their conjugates, FAP-CAR T cells, and FAP vaccines. A unique enzymatic activity and selective expression in tumor microenvironment make FAP a promising therapeutic target. A better understanding of its role in individual tumor types, careful selection of patients, and identification of suitable combinations with currently available anticancer treatments will be critical for a successful translation of preclinically tested approaches of FAP targeting into clinical setting.

• MeSH
• cílená molekulární terapie metody   MeSH
• endopeptidasy MeSH
• inhibitory enzymů terapeutické užití   MeSH
• lidé MeSH
• membránové proteiny antagonisté a inhibitory   genetika   metabolismus   MeSH
• nádorové mikroprostředí účinky léků   genetika   MeSH
• nádory farmakoterapie   genetika   metabolismus   MeSH
• regulace genové exprese enzymů účinky léků   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• serinové endopeptidasy genetika   metabolismus   MeSH
• želatinasy antagonisté a inhibitory   genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• endopeptidasy MeSH
• fibroblast activation protein alpha MeSH Prohlížeč
• inhibitory enzymů MeSH
• membránové proteiny MeSH
• serinové endopeptidasy MeSH
• želatinasy MeSH

The lack of specificity of traditional cytostatics and increasing resistance of cancer cells represent important challenges in cancer therapy. One of the characteristics of cancer cells is their intrinsic oxidative stress caused by higher metabolic activity, mitochondrial malfunction, and oncogene stimulation. This feature can be exploited in the pursuit of more selective cancer therapy, as there is increasing evidence that cancer cells are more sensitive to elevated concentrations of reactive oxygen species than normal cells. In this study, we demonstrate a new concept for cancer cell targeting by in situ production of radicals under physiological conditions. The biologically active radicals are produced in the milieu of cancer cells by enzymatic conversion from an inactive precursor, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)diammonium salt, by using miniature bioreactors represented by cell-sized microgels containing immobilized laccase. We utilize the pH-dependent activity of laccase to generate radicals only at a lower pH (5.7-6.1) that is characteristic of the tumor microenvironment. The composition of the microgels was optimized so as to allow sufficient substrate and radical diffusion, high enzyme activity, and stability under physiological conditions. The functionality of this system was evaluated on three cancer cell lines (HeLa, HT-29, and DLD1) and the cytotoxicity of in situ-produced radicals was successfully proven in all cases. These results demonstrate that cancer cell targeting by in situ-generated radicals using miniature enzymatic reactors may represent an alternative to traditional cytostatics. In particular, the pH-dependence of radical generation and their short-lived nature can ensure localized functionality in the tumor microenvironment and thereby reduce systemic side-effects.

• Klíčová slova
• Spray-drying, cancer cell targeting, cytotoxicity, immobilization, laccase, microgel, microparticles, oxidative stress, pH-dependence, radicals,
• MeSH
• bioreaktory * MeSH
• buňky HT-29 MeSH
• HeLa buňky MeSH
• koncentrace vodíkových iontů MeSH
• lakasa metabolismus   MeSH
• lidé MeSH
• mikrogely chemie   MeSH
• nádorové mikroprostředí účinky léků   MeSH
• oxidační stres MeSH
• reaktivní formy kyslíku metabolismus   farmakologie   MeSH
• velikost částic MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• lakasa MeSH
• mikrogely MeSH
• reaktivní formy kyslíku MeSH

Several strategies have been developed to fight viral infections, not only in humans but also in animals and plants. Some of them are based on the development of efficient vaccines, to target the virus by developed antibodies, others focus on finding antiviral compounds with activities that inhibit selected virus replication steps. Currently, there is an increasing number of antiviral drugs on the market; however, some have unpleasant side effects, are toxic to cells, or the viruses quickly develop resistance to them. As the current situation shows, the combination of multiple antiviral strategies or the combination of the use of various compounds within one strategy is very important. The most desirable are combinations of drugs that inhibit different steps in the virus life cycle. This is an important issue especially for RNA viruses, which replicate their genomes using error-prone RNA polymerases and rapidly develop mutants resistant to applied antiviral compounds. Here, we focus on compounds targeting viral structural capsid proteins, thereby inhibiting virus assembly or disassembly, virus binding to cellular receptors, or acting by inhibiting other virus replication mechanisms. This review is an update of existing papers on a similar topic, by focusing on the most recent advances in the rapidly evolving research of compounds targeting capsid proteins of RNA viruses.

• Klíčová slova
• antiviral compounds, antivirals, assembly inhibitor, capsid assembly, capsid binding, capsid targeting, virus inhibitor,
• MeSH
• antivirové látky chemie   farmakologie   MeSH
• infekce RNA viry farmakoterapie   virologie   MeSH
• lidé MeSH
• replikace viru účinky léků   MeSH
• RNA-viry účinky léků   fyziologie   MeSH
• sestavení viru účinky léků   MeSH
• virové plášťové proteiny antagonisté a inhibitory   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• antivirové látky MeSH
• virové plášťové proteiny MeSH