Camptothecin (CPT), an alkaloid, was first discovered from plants and has potent anti-tumor activity. Since then, CPT analogs (namely Irinotecan and Topotecan) have been approved by the FDA for cancer treatments. Curcumin, on the other hand, is a widely used photosensitizer in photodynamic therapy (PDT) treatment. In our previous work, we have reported a straightforward strategy to construct a drug self-delivery system in which two-molecular species Irinotecan and Curcumin can self-assembly into a complex of ion pairs, namely ICN, through intermolecular non-covalent interactions. We found that ICN has slightly better chemotherapy efficacy than its individual components with much fewer side effects. In this paper, we aim to combine the chemotherapy and the PDT of ICN to further improve its anti-tumor performance. The efficient cellular uptake of ICNs was observed by confocal microscopy. Dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay was used to detect the generation of singlet oxygen species. We found that the cell viability was 9% with both chemotherapy and PDT, and 31% with chemotherapy alone for the case with an ICN concentration of 10 μM, which demonstrated that the anti-tumor efficacy against the HT-29 cancer cell line was enhanced substantially with the combination therapy strategy. The study with an in vivo mouse model has further verified that the chemo-PDT dual therapy can inhibit tumor growth by 84% and 18.8% comparing with the control group and the chemotherapy group, respectively. Our results demonstrated that the new strategy using self-assembly and carrier-free nanoparticles with their chemo-PDT dual therapy may provide new opportunities to develop future combinatorial therapy methods in treating cancer.

• Klíčová slova
• Anti-tumor efficacy, Combination therapy, Drug delivery system, Photodynamic therapy,
• MeSH
• apoptóza účinky léků   účinky záření   MeSH
• buňky HT-29 MeSH
• diarylheptanoidy chemie   MeSH
• fotochemoterapie metody   MeSH
• intracelulární prostor účinky léků   metabolismus   účinky záření   MeSH
• kamptothecin chemie   farmakologie   MeSH
• kombinovaná terapie MeSH
• lidé MeSH
• protinádorové látky chemie   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• diarylheptanoidy MeSH
• kamptothecin MeSH
• protinádorové látky MeSH

The present study was performed to evaluate the antibacterial activities of an antimicrobial peptide (CSpK14) and the synergies thereof with β-lactams against vancomycin-resistant Staphylococcus aureus (VRSA) and Enterococci (VRE). Our strain was isolated from fermented food (kimchi), which is 99.79 % homologous with Bacillus amyloliquefaciens subsp. plantarum FZB42(T). CSpK14 was purified to homogeneity by diammonium sulfate precipitation, concentration, dialysis, and followed by two-stage chromatographic separation, i.e., Sepharose Cl-6B and Sephadex G-25 chromatography, and had a molar mass of ~4.6 kDa via Tricine SDS-PAGE and in situ examination. It was stable at pH 6.0-11.5 and temperature up to 80 °C. In addition, it was also stable with various metal ions, solvents, and proteases. The N-terminal amino acid sequence was H-Y-D-P-G-D-D-S-G-N-T-G and did not show any significant homology with reported peptides. However, it shows some degrees of identity with alpha-2-macroglobulin and ligand-gated channel protein from different microorganisms. CSpK14 significantly reduced the minimum inhibitory concentrations (MICs) of β-lactams and had no effect on non-β-lactams against VRSA and VRE. MICs of CSpK14/oxacillin and CSpK14/ampicillin were reduced by 8- to 64-fold and 2- to 16-fold, respectively. The time killing assay between CSpK14/oxacillin (2.29-2.37 Δlog10CFU/mL at 24 h) and CSpK14/ampicillin (2.30-2.38 Δlog10CFU/mL at 24 h) being >2-fold and fractional inhibitory concentration index ˂0.5 revealed synergy. Furthermore, the biofilms formed by VRSA and VRE were reduced completely. CSpK14 was simple to purify, had low molecular mass, was stable over a wide pH range or tested chemicals, had broad inhibitory spectrum, and possessed potent synergistic antimicrobial-antibiofilm properties. CSpK14 synergistically enhanced the efficacy of β-lactams and is therefore suitable for combination therapy.

• MeSH
• ampicilin farmakologie   MeSH
• antibakteriální látky biosyntéza   izolace a purifikace   farmakologie   MeSH
• Bacillus amyloliquefaciens klasifikace   imunologie   metabolismus   MeSH
• biofilmy účinky léků   růst a vývoj   MeSH
• chromatografie iontoměničová MeSH
• enterokoky rezistentní vůči vankomycinu účinky léků   růst a vývoj   MeSH
• fylogeneze MeSH
• kationické antimikrobiální peptidy biosyntéza   izolace a purifikace   farmakologie   MeSH
• kombinovaná farmakoterapie MeSH
• mikrobiální testy citlivosti MeSH
• oxacilin farmakologie   MeSH
• rezistence na vankomycin účinky léků   MeSH
• sekvence aminokyselin MeSH
• stabilita proteinů MeSH
• Staphylococcus aureus účinky léků   růst a vývoj   MeSH
• synergismus léků MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ampicilin MeSH
• antibakteriální látky MeSH
• kationické antimikrobiální peptidy MeSH
• oxacilin MeSH

Galectin-3 (Gal-3), a member of the β-galactoside-binding lectin family, is a tumor biomarker and involved in tumor angiogenesis and metastasis. Gal-3 is therefore considered as a promising target for early cancer diagnosis and anticancer therapy. We here present the synthesis of a library of tailored multivalent neo-glycoproteins and evaluate their Gal-3 binding properties. By the combinatorial use of glycosyltransferases and chemo-enzymatic reactions, we first synthesized a set of N-acetyllactosamine (Galβ1,4GlcNAc; LacNAc type 2)-based oligosaccharides featuring five different terminating glycosylation epitopes, respectively. Neo-glycosylation of bovine serum albumin (BSA) was accomplished by dialkyl squarate coupling to lysine residues resulting in a library of defined multivalent neo-glycoproteins. Solid-phase binding assays with immobilized neo-glycoproteins revealed distinct affinity and specificity of the multivalent glycan epitopes for Gal-3 binding. In particular, neo-glycoproteins decorated with N',N″-diacetyllactosamine (GalNAcβ1,4GlcNAc; LacdiNAc) epitopes showed high selectivity and were demonstrated to capture Gal-3 from human serum with high affinity. Furthermore, neo-glycoproteins with terminal biotinylated LacNAc glycan motif could be utilized as Gal-3 detection agents in a sandwich enzyme-linked immunosorbent assay format. We conclude that, in contrast to antibody-based capture steps, the presented neo-glycoproteins are highly useful to detect functionally intact Gal-3 with high selectivity and avidity. We further gain novel insights into the binding affinity of Gal-3 using tailored multivalent neo-glycoproteins, which have the potential for an application in the context of cancer-related biomedical research.

• MeSH
• aminocukry chemická syntéza   chemie   metabolismus   MeSH
• galektin 3 antagonisté a inhibitory   metabolismus   MeSH
• glykoproteiny chemická syntéza   chemie   metabolismus   farmakologie   MeSH
• glykosylace MeSH
• lidé MeSH
• ligandy MeSH
• oligosacharidy chemická syntéza   chemie   metabolismus   MeSH
• sérový albumin hovězí chemická syntéza   chemie   metabolismus   farmakologie   MeSH
• skot MeSH
• techniky kombinatorické chemie MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• skot MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aminocukry MeSH
• galektin 3 MeSH
• glykoproteiny MeSH
• ligandy MeSH
• N-acetyllactosamine MeSH Prohlížeč
• oligosacharidy MeSH
• sérový albumin hovězí MeSH

Treatment of blood malignancies and other cancer diseases has been mostly unfeasible, so far. Therefore, novel treatment regimens should be developed and the currently used ones should be further elaborated. A stable component in various cancer treatment regimens consists of vincristine, an antimitotic compound of natural origin. Despite its strong anticancer activity, mostly, it cannot be administered as monotherapy due to its unspecific action and severe side effects. However, vincristine is suitable for combination therapy. Multidrug treatment regimens including vincristine are standardly applied in the therapy of non-Hodgkin lymphoma and other malignancies, in which it is combined with drugs of different mechanisms of action, mainly with DNA-interacting compounds (for example cyclophosphamide), or drugs interfering with DNA synthesis (for example methotrexate). Besides, co-administration of vincristine with monoclonal antibodies has also emerged, the typical example of which is the anti-CD20 antibody rituximab. Although in some combination anticancer therapies, vincristine has been replaced with other drugs exhibiting lesser side effects, though, in most cases, it is still irreplaceable. This is strongly evidenced by the number of active clinical trials evaluating vincristine in combination cancer therapy. Therefore, in this article, we have reviewed the most common cancer treatment regimens employing vincristine and bring an overview of current trends in the clinical development of this compound.

• Klíčová slova
• antibodies, antimitotics, combinatorial treatment, cyclophosphamide, dacarbazine, doxorubicin, etoposide, procarbazine, topotecan, vinca alkaloids,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Spinal cord injury (SCI) is a devastating traumatic injury resulting in paralysis or sensory deficits due to tissue damage and the poor ability of axons to regenerate across the lesion. Despite extensive research, there is still no effective treatment that would restore lost function after SCI. A possible therapeutic approach would be to bridge the area of injury with a bioengineered scaffold that would create a stimulatory environment as well as provide guidance cues for the re-establishment of damaged axonal connections. Advanced scaffold design aims at the fabrication of complex materials providing the concomitant delivery of cells, neurotrophic factors or other bioactive substances to achieve a synergistic effect for treatment. This review summarizes the current utilization of scaffolding materials for SCI treatment in terms of their physicochemical properties and emphasizes their use in combination with various cell types, as well as with other combinatorial approaches promoting spinal cord repair.

• MeSH
• biokompatibilní materiály farmakologie   MeSH
• buněčná a tkáňová terapie * MeSH
• lékové transportní systémy MeSH
• lidé MeSH
• polymery farmakologie   MeSH
• poranění míchy terapie   MeSH
• tkáňové podpůrné struktury chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• biokompatibilní materiály MeSH
• polymery MeSH

The current pharmacological pretreatment and medical treatment of nerve agent poisoning is an insufficiently addressed medical task. The prophylactic efficacy of a novel compound acting dually as an acetylcholinesterase inhibitor and NMDA receptor antagonist (K1959) and the therapeutic efficacy of a novel NMDA receptor antagonist (K2060) were evaluated in the NMRI mice model of nerve agent poisoning by tabun, soman and sarin. Their added value to the standard antidotal treatment (a combination of oxime reactivator and atropine) was also analyzed. The novel dually acting prophylactic drug (K1959) did not bring any additional benefit compared to the commonly used pyridostigmine. By contrast, an increase in the therapeutic efficacy of classic antidotal treatment was observed when the novel NMDA receptor antagonist (K2060) was combined with commonly used antidotes (oxime reactivator in combination with atropine). This novel combination reduced the acute toxicity of tabun, soman, and sarin more than two-fold, four-fold, and five-fold, respectively. These results highlight the possibility of NMDA antagonists such as K2060 as a supportive drug for the classic therapy of organophosphorus poisoning.

• Klíčová slova
• Acetylcholinesterase inhibition, Atropine, In vivo testing, NMDA receptor antagonist, Nerve agent, Organophosphorus intoxication, Oxime reactivator, Prophylaxis,
• MeSH
• antidota * farmakologie   MeSH
• atropin farmakologie   terapeutické užití   MeSH
• cholinesterasové inhibitory * farmakologie   MeSH
• modely nemocí na zvířatech * MeSH
• myši MeSH
• nervová bojová látka * otrava   toxicita   MeSH
• organofosfáty MeSH
• otrava organofosfáty farmakoterapie   prevence a kontrola   MeSH
• oximy farmakologie   terapeutické užití   MeSH
• reaktivátory cholinesterasy farmakologie   terapeutické užití   MeSH
• receptory N-methyl-D-aspartátu * antagonisté a inhibitory   metabolismus   MeSH
• sarin toxicita   otrava   MeSH
• soman * otrava   toxicita   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antidota * MeSH
• atropin MeSH
• cholinesterasové inhibitory * MeSH
• nervová bojová látka * MeSH
• organofosfáty MeSH
• oximy MeSH
• reaktivátory cholinesterasy MeSH
• receptory N-methyl-D-aspartátu * MeSH
• sarin MeSH
• soman * MeSH
• tabun MeSH Prohlížeč

Multiple myeloma (MM) has witnessed improved patient outcomes through advancements in therapeutic approaches. Notably, allogeneic stem cell transplantation, proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies have contributed to enhanced quality of life. Recently, a promising avenue has emerged with chimeric antigen receptor (CAR) T cells targeting B-cell maturation antigen (BCMA), expressed widely on MM cells. To mitigate risks associated with allogenic T cells, we investigated the potential of BCMA CAR expression in natural killer cells (NKs), known for potent cytotoxicity and minimal side effects. Using the NK-92 cell line, we co-expressed BCMA CAR and soluble tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) employing the piggyBac transposon system. Engineered NK cells (CAR-NK-92-TRAIL) demonstrated robust cytotoxicity against a panel of MM cell lines and primary patient samples, outperforming unmodified NK-92 cells with a mean difference in viability of 45.1% (±26.1%, depending on the target cell line). Combination therapy was explored with the proteasome inhibitor bortezomib (BZ) and γ-secretase inhibitors (GSIs), leading to a significant synergistic effect in combination with CAR-NK-92-TRAIL cells. This synergy was evident in cytotoxicity assays where a notable decrease in MM cell viability was observed in combinatorial therapy compared to single treatment. In summary, our study demonstrates the therapeutic potential of the CAR-NK-92-TRAIL cells for the treatment of MM. The synergistic impact of combining these engineered NK cells with BZ and GSI supports further development of allogeneic CAR-based products for effective MM therapy.

• Klíčová slova
• allogenic, cancer, chimeric antigen receptor, immunotherapy, multiple myeloma, natural killer,
• MeSH
• bortezomib farmakologie   terapeutické užití   MeSH
• chimerické antigenní receptory * metabolismus   MeSH
• imunoterapie adoptivní MeSH
• kvalita života MeSH
• lidé MeSH
• maturační antigen B-buněk metabolismus   MeSH
• mnohočetný myelom * patologie   terapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• bortezomib MeSH
• chimerické antigenní receptory * MeSH
• maturační antigen B-buněk MeSH

DNA methylation plays a pivotal role in the etiology of cancer by mediating epigenetic silencing of cancer-related genes. Since the relationship between aberrant DNA methylation and cancer has been understood, there has been an explosion of research at developing anti-cancer therapies that work by inhibiting DNA methylation. From the discovery of first DNA hypomethylating drugs in the 1980s to recently discovered second generation pro-drugs, exceedingly large number of studies have been published that describe the DNA hypomethylation-based anti-neoplastic action of these drugs in various stages of the pre-clinical investigation and advanced stages of clinical development. This review is a comprehensive report of the literature published in past 40 years, on so far discovered nucleosidic DNA methylation inhibitors in chronological order. The review will provide a complete insight to the readers about the mechanisms of action, efficacy to demethylate and re-express various cancer-related genes, anti-tumor activity, cytotoxicity profile, stability, and bioavailability of these drugs. The review further presents the far known mechanisms of primary and secondary resistance to azanucleoside drugs. Finally, the review highlights the ubiquitous role of DNA hypomethylating epi-drugs as chemosensitizers and/or priming agents, and recapitulate the combinatorial cancer preventive effects of these drugs with other epigenetic agents, conventional chemo-drugs, or immunotherapies. This comprehensive review analyzes the beneficial characteristics and drawbacks of nucleosidic DNA methylation inhibitors, which will assist the pre-clinical and clinical researchers in the design of future experiments to improve the therapeutic efficacy of these drugs and circumvent the challenges in the path of successful epigenetic therapy.

• Klíčová slova
• Combinatorial therapy, DNA hypermethylation, DNA methyltransferase inhibitors, Drug resistance, Gene silencing, Nucleoside analogs,
• MeSH
• azacytidin analogy a deriváty   farmakologie   MeSH
• chemorezistence MeSH
• DNA-(cytosin-5)-methyltransferasa 1 antagonisté a inhibitory   MeSH
• lidé MeSH
• metylace DNA účinky léků   MeSH
• nukleosidy farmakologie   MeSH
• objevování léků * MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• thioguanin farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• azacytidin MeSH
• DNA-(cytosin-5)-methyltransferasa 1 MeSH
• guadecitabine MeSH Prohlížeč
• nukleosidy MeSH
• protinádorové látky MeSH
• thioguanin MeSH

Malignant astrogliomas are among the most aggressive, highly vascular and infiltrating tumours bearing a dismal prognosis, mainly due to their resistance to current radiation treatment and chemotherapy. Efforts to identify and target the mechanisms that underlie astroglioma resistance have recently focused on candidate cancer stem cells, their biological properties, interplay with their local microenvironment or 'niche', and their role in tumour progression and recurrence. Both paracrine and autocrine regulation of astroglioma cell behaviour by locally produced cytokines such as the vascular endothelial growth factor (VEGF) are emerging as key factors that determine astroglioma cell fate. Here, we review these recent rapid advances in astroglioma research, with emphasis on the significance of VEGF in astroglioma stem-like cell biology. Furthermore, we highlight the unique DNA damage checkpoint properties of the CD133-marker-positive astroglioma stem-like cells, discuss their potential involvement in astroglioma radioresistance, and consider the implications of this new knowledge for designing combinatorial, more efficient therapeutic strategies.

• MeSH
• antigen AC133 MeSH
• astrocytom metabolismus   terapie   MeSH
• CD antigeny metabolismus   MeSH
• glykoproteiny metabolismus   MeSH
• lidé MeSH
• nádorové kmenové buňky metabolismus   účinky záření   MeSH
• nádory mozku metabolismus   terapie   MeSH
• peptidy metabolismus   MeSH
• poškození DNA MeSH
• tolerance záření MeSH
• vaskulární endoteliální růstový faktor A metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• antigen AC133 MeSH
• CD antigeny MeSH
• glykoproteiny MeSH
• peptidy MeSH
• PROM1 protein, human MeSH Prohlížeč
• vaskulární endoteliální růstový faktor A MeSH

The Connective Tissue Oncology Group Annual Meeting 2018 (CTOS 2018) took place in Rome from 4 to 17 November 2018, and the 39th Plenary Meeting of the Scandinavian Sarcoma Group (SSGM 2019) was held in Bergen from 8 to 10 May 2019. These two large international conferences brought together an overwhelming majority of molecular and clinical specialists in the sarcoma field, especially those working on soft tissue sarcoma. Topics discussed on the conferences included, among others, sarcoma genetics, clinical and molecular subclassification, targeted therapy, clinical prognostication, and new experimental sarcoma models. A large ongoing international study on germinal sarcoma genetics was presented, the interim results of which revealed the extremely complex nature of genetic disposition to sarcoma, and, surprisingly, a rather prominent place among predisposing genes for those coding for structural telomere constituents. Fusion oncogenes dominate somatic sarcoma genetics, especially because of their origin and impact on sarcoma clinical behaviour, and are especially relevant for karyotypically simple paediatric sarcomas. A crucial issue in karyotypically complex sarcomas are the efforts being made to obtain a subclassification of sarcoma, other than those based on pathology, using either the clinical characteristics of sarcomas (uterine leiomyosarcoma vs. soft tissue leiomyosarcoma) or specific gene expression profiles (molecular subtypes in undifferentiated pleiomorphic sarcoma), which showed that molecular characterization can open the way for subtype specific therapies. Other examples of where this type of strategy can be applied include gastrointestinal stromal tumours, infantile fibrosarcoma, and inflammatory myofibroblastic tumours, where targeted therapy could be conceived based on the actionable mutations identified. Attempts in this direction have been made also for clear cell sarcoma and dedifferentiated liposarcoma, albeit the effectiveness of molecular-targeted treatments for these sarcomas is still poor, and progress in the treatment of osteosarcoma is still rather slow. Actually, the platelet-derived growth factor signalling system holds a prominent position in searches for targeted therapies, not only against rare sarcoma types, where are activated by mutations (some gastrointestinal stromal tumours, infantile hereditary myofibromatosis, and dermatofibrosarcoma protuberans), but also against other more usual sarcoma types, where the blocking anti-PDGFRα-antibody olaratumab has been successfully integrated into combinatorial chemotherapeutic regimens. In the field of clinical prognostication, remarkable progress in sarcoma nomograms was reported. Interesting results were also presented in the area of new experimental sarcoma models. Participation on both scientifi c conferences and all the experimental work leading to the presented sarcoma models were supported by the Czech Science Foundation project No. 17-17636S. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 20. 9. 2019 Accepted: 6. 11. 2019.

• Klíčová slova
• chondrosarcoma, experimental sarcoma models, genetic predisposition, molecular subtypes, osteosarcoma, prognostic nomograms, soft tissue sarcomas, targeted therapy,
• MeSH
• cílená molekulární terapie MeSH
• lidé MeSH
• nádory měkkých tkání * klasifikace   genetika   terapie   MeSH
• sarkom * klasifikace   genetika   terapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• kongresy MeSH