المؤلفون: Martyna Korcz, Lukasz Sitek, Franciszek Saczewski, Ewa Romejko, Patrick J. Bednarski, Monika Wojciechowska, Anita Kornicka, Piotr Szumlas, Aneta Sakowicz

المصدر: Medicinal Chemistry. 13

مصطلحات موضوعية: Indazoles, Stereochemistry, Phenylurea Compounds, Thiourea, Cancer, Antineoplastic Agents, Biological activity, medicine.disease, In vitro, chemistry.chemical_compound, chemistry, Cell culture, Cell Line, Tumor, Drug Discovery, Cancer cell, medicine, Humans, Cytotoxic T cell, Cytotoxicity

الوصف: Background N-substituted 3-amino-1H-indazoles represent an interesting class of biologically active compounds. Among them, derivatives containing phenylurea moiety are of particular interest. Such compounds have been found to possess inhibitory activity against cancer cell growth. Additionally, various oxazoline-containing compounds have also been designed as potential anticancer agents. Objective The aim of this work was to obtain a new class of N-substituted 3-amino-1H-indazole derivatives with cytotoxic activity towards cancer cells. Method Two series of 1-[1-(4,5-dihydrooxazol-2-yl)-1H-indazol-3-yl]-3-phenylurea and 3- phenylthiourea derivatives 7-17 and 18-22, respectively, were prepared and screened for their potential in vitro cytotoxic activities against lung carcinoma LCLC-103H cell line using a crystal violet microtiter plate assay. Results All the urea derivatives, except the compound 8, were inactive at a concentration of 20 μM attainable in cancer cells, while the thiourea derivatives showed a pronounced cancer cell growth inhibitory effects. The most potent 1-[1-(4,5-dihydrooxazol-2-yl)-1H-indazol-3-yl]-3-ptolylthiourea (19) exhibited cytotoxicity on the lung cancer LCLC-103H and cervical cancer SISO cell lines at a concentration of 10 µM. Moreover, compound 19 displayed cytostatic activity against pancreas cancer DAN-G cell line. Conclusion The 1-[1-(4,5-dihydrooxazol-2-yl)-1H-indazol-3-yl]-3-phenylthiourea derivatives described herein may serve as a useful scaffold for the search for novel anticancer agents.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ff859797b8d0607693e0ec58d4c8adbeTest
https://doi.org/10.2174/1573406413666170306114401Test

المؤلفون: Łukasz Balewski, Franciszek Sączewski, Maria Gdaniec, Patrick J. Bednarski, Anna Makowska, Ewa Borys

المصدر: Molecules, Vol 19, Iss 10, Pp 17026-17051 (2014)
Molecules
Volume 19
Issue 10
Pages 17026-17051

مصطلحات موضوعية: Models, Molecular, Stereochemistry, Pharmaceutical Science, chemistry.chemical_element, Antineoplastic Agents, 1-(2-pyridyl)imidazolidin-2-ones, Crystallography, X-Ray, Article, Analytical Chemistry, X-ray crystal structure analysis, lcsh:QD241-441, chemistry.chemical_compound, X-Ray Diffraction, lcsh:Organic chemistry, Coordination Complexes, Neoplasms, copper(II) complexes, Drug Discovery, Pyridine, Organometallic Compounds, Tumor Cells, Cultured, in vitro antitumor activity, Humans, Viability assay, Crystal violet, Physical and Theoretical Chemistry, Alkyl, Group 2 organometallic chemistry, chemistry.chemical_classification, Organic Chemistry, Thiones, Copper, In vitro, chemistry, Chemistry (miscellaneous), X-ray crystallography, 1-(2-pyridyl)imidazolidine-2-thiones, Molecular Medicine

الوصف: Six series of structurally different mono- and binuclear copper(II) complexes 5–10 were obtained by reacting N-(2-pyridyl)imidazolidin-2-ones (1a–l), N,N'-bis(2-pyridyl)imidazolidin-2-ones (2a,b), N-acyl-N'(2-pyridyl)imidazolodin-2-ones (3a–j) and N-(2-pyridyl)imidazolidine-2-thiones (4a–g) with copper(II) chloride at an ambient temperature. The coordination modes of the complexes obtained were established by elemental analysis, IR spectroscopic data and single crystal X-ray diffraction studies. The in vitro cytotoxic activities of both the free ligands and copper(II) complexes were evaluated using a crystal violet microtiter plate assay on five human tumor cell lines: LCLC-103H, A-427, SISO, RT-4 and DAN-G. The free ligands 1–4 at concentration attainable in cancer cells of 20 μM showed no meaningful cytotoxic effect with cell viability in the range of 88%–100%. The most potent copper(II) complex of 1-(6-ethoxy-2-pyridyl)imidazolidin-2-one (6b) exhibited selective cytotoxicity against A-427 lung cancer cell line, while the complexes of 1-(5-methyl-2-pyridyl)imidazolidine-2-thione (5h) and 1-(4-tert-butyl-2-pyridyl)imidazolidine-2-thione (5j) showed cytostatic effect against a whole panel of five human tumor cell lines. In conclusion, the only complexes that showed remarkably increased activity in comparison to the free ligands were those obtained from N-(2-pyridyl)imidazolidine-2-thiones 4c and 4e substituted with alkyl group at position 4 or 5 of pyridine ring.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::444461dc96c1061544f8a1c82fa2fe59Test
http://www.mdpi.com/1420-3049/19/10/17026Test

المؤلفون: Zsolt Sziklavari, Patrick J. Bednarski, Reiner Neu, Michael Ried, Hans-Stefan Hofmann, Claudius Diez, Karla Lehle

المصدر: European Journal of Cardio-Thoracic Surgery. 47:563-566

مصطلحات موضوعية: Mesothelioma, Pulmonary and Respiratory Medicine, Hyperthermia, Lung Neoplasms, Pleural Neoplasms, medicine.medical_treatment, Antineoplastic Agents, Models, Biological, Human lung, Parenchyma, Humans, Medicine, Pneumonectomy, Lung, Cisplatin, Chemotherapy, business.industry, Hyperthermia, Induced, General Medicine, Penetration (firestop), medicine.disease, medicine.anatomical_structure, Chemotherapy, Cancer, Regional Perfusion, Surgery, Cardiology and Cardiovascular Medicine, business, Nuclear medicine, Perfusion, Ex vivo, medicine.drug

الوصف: OBJECTIVES The effects of cisplatin on the lung parenchyma during hyperthermic intrathoracic chemotherapy perfusion have not been analysed in detail. The objective of this study was to evaluate both the concentration and depth of the penetration of cisplatin in human lung tissue after hyperthermic exposure under ex vivo conditions. METHODS This experimental study was approved by the local ethics committee. Twelve patients underwent pulmonary wedge resections after elective thoracic lobectomies were performed (resected lobe), and the lung tissue (approximately 1-2 cm(3)) was incubated (in vitro) with cisplatin (0.05 mg/ml; 60 min, 42°C). Subsequent tissue beds (depth, 0.5 mm; median weight, 70-92 mg) were prepared from the outside to the middle, and the amount of cisplatin per tissue weight was analysed using atomic absorption spectrometry. Afterwards, the penetration of cisplatin depth was calculated and related to the different concentrations per tissue. RESULTS Cisplatin penetrated into the human lung tissue after ex vivo hyperthermic exposure. The median amount of platinum [nmol cisplatin/g lung tissue] decreased significantly (P ≤ 0.05) depending on the penetration depth: 32 nmol/g (1 mm), 20 nmol/g (2 mm) and 6.8 nmol/g (4 mm). The calculated median concentrations of cisplatin (µg/ml) were 2.4 µg/ml (1 mm), 1.4 µg/ml (2 mm) and 0.5 µg/ml (4 mm), respectively. CONCLUSIONS Under ex vivo hyperthermic conditions, cisplatin diffused into human lung tissue. The median penetration depth of the cisplatin was approximately 3-4 mm. The penetration of cisplatin into lung tissue may affect the local therapy of residual tumour cells on the lung surface using hyperthermic intrathoracic chemotherapy perfusion in patients with malignant pleural tumours.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c4f8a28bdaff00c401ab033b2a1d5be6Test
https://doi.org/10.1093/ejcts/ezu217Test

المؤلفون: Kim S. Robinson, Luca Salassa, Virginia Appleyard, Karen Murray, Katharina Korpis, Aron F. Westendorf, Nicola J. Farrer, Renate Grünert, Peter J. Sadler, Julie A. Woods, Alastair M. Thompson, Patrick J. Bednarski

المصدر: Molecular Cancer Therapeutics

مصطلحات موضوعية: Cancer Research, Programmed cell death, Organoplatinum Compounds, Cell Survival, Ultraviolet Rays, Mice, Nude, Antineoplastic Agents, Apoptosis, HL-60 Cells, 010402 general chemistry, 01 natural sciences, Article, Inhibitory Concentration 50, Mice, chemistry.chemical_compound, Annexin, Autophagy, medicine, Animals, Humans, Cytotoxic T cell, Propidium iodide, Clonogenic assay, Cell Shape, Cisplatin, 010405 organic chemistry, Cell Cycle, Photochemical Processes, Xenograft Model Antitumor Assays, 0104 chemical sciences, Oncology, chemistry, Drug Resistance, Neoplasm, Cell culture, Immunology, Biophysics, Female, medicine.drug

الوصف: Photoactivatable PtIV diazido complexes have unusual photobiologic properties. We show here that trans,trans,trans-[PtIV(N3)2(OH)2(py)(NH3)] complex 3 is a potent photoactivated cytotoxin toward human cancer cells in culture, with an average IC50 value in 13 cell lines of 55 ± 28 μmol/L after 30 minutes (0.12 mW/cm2) photoactivation with UVA, although visible light was also effective. Photoactivated complex 3 was noncross-resistant to cisplatin in 3 of 4 resistant cell lines. Cell swelling but very little blebbing was seen for HL60 cells treated with irradiated complex 3. Unlike cisplatin and etoposide, both of which cause apoptosis in HL60 cells, no apoptosis was observed for UVA-activated complex 3 by the Annexin V/propidium iodide flow cytotometry assay. Changes in the levels of the autophagic proteins LC3B-II and p62 in HL60 cells treated with UVA-activated complex 3 indicate autophagy is active during cell death. In a clonogenic assay with the SISO human cervix cancer cell line, 3 inhibited colony formation when activated by UVA irradiation. Antitumor activity of complex 3 in mice bearing xenografted OE19 esophageal carcinoma tumors was photoaugmented by visible light. Insights into the novel reaction pathways of complex 3 have been obtained from 14N{1H} nuclear magnetic resonance studies, which show that photoactivation pathways can involve release of free azide in buffered solution. Density functional theory (DFT) and time-dependent DFT calculations revealed the dissociative character of singlet and triplet excited states of complex 3, which gives rise to reactive, possibly cytotoxic azidyl radicals. Mol Cancer Ther; 11(9); 1894–904. ©2012 AACR.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::96b41f080da70ff3f659c50f6473774bTest
https://doi.org/10.1158/1535-7163.mct-11-0959Test

المؤلفون: Marta Maria Natile, Giovanni Natile, Stefanie Perfahl, Patrick J. Bednarski, Carola Schulzke, Christiane A. Helm, Heba S. Mohamad

المصدر: Molecular pharmaceutics
13 (2016): 2346–2362. doi:10.1021/acs.molpharmaceut.6b00108
info:cnr-pdr/source/autori:Perfahl S.; Natile M.M.; Mohamad H.S.; Helm C.A.; Schulzke C.; Natile G.; Bednarski P.J./titolo:Photoactivation of Diiodido-Pt(IV) Complexes Coupled to Upconverting Nanoparticles/doi:10.1021%2Facs.molpharmaceut.6b00108/rivista:Molecular pharmaceutics (Print)/anno:2016/pagina_da:2346/pagina_a:2362/intervallo_pagine:2346–2362/volume:13

مصطلحات موضوعية: Organoplatinum Compounds, Photochemistry, Pharmaceutical Science, Antineoplastic Agents, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, chemistry.chemical_compound, Microscopy, Electron, Transmission, X-Ray Diffraction, Cell Line, Tumor, Drug Discovery, Humans, Peptide bond, Prodrugs, Upconverting nanoparticles, Carboxylate, photoactivated chemotherapy, Cytotoxicity, Chemistry, DNA, Prodrug, 021001 nanoscience & nanotechnology, 0104 chemical sciences, upconverting nanoparticles, Nanocrystal, Covalent bond, photoactivatable Pt complexes, anticancer prodrug, Nanoparticles, Molecular Medicine, Surface modification, 0210 nano-technology

الوصف: The preparation, characterization, and surface modification of upconverting lanthanide-doped hexagonal NaGdF4 nanocrystals attached to light sensitive diiodido Pt(IV) complexes is presented. The evaluation for photo activation and cytotoxicity of the novel carboxylated diiodido Pt(IV) cytotoxic prodrugs by near-infrared (NIR) light (2 = 980 nm) is also reported. We attempted two different strategies for attachment of light-sensitive diiodido Pt(IV) complexes to Yb,Er- and Yb,Tm-doped beta-NaGdF4 upconverting nanoparticles (UCNPs) in order to provide nanohybrids, which offer unique opportunities for selective drug activation within the tumor cells and subsequent spatiotemporal controlled drug release by NIR-to-visible light-upconversion: (A) covalent attachment of the Pt(IV) complex via amide bond formation and (B) carboxylate exchange of oleate on the surface of the UCNPs with diiodido Pt(IV) carboxylato complexes. Initial feasibility studies showed that NIR applied by a 980 nm laser had only a slight effect on the stability of the various diiodido Pt(IV) complexes, but when UCNPs were present more rapid loss of the ligand metal charge transfer (LMCT) bands of the diiodido Pt(IV) complexes was observed. Furthermore, Pt released from the Pt(IV) complexes platinated calf-thymus DNA (ct-DNA) more rapidly when NIR was applied compared to dark controls. Of the two attachment strategies, method A with the covalently attached diiodido Pt(IV) carboxylates via amide bond formation proved to be the most effective method for generating UCNPs that release Pt when irradiated with NIR; the released Pt was also able to bind irreversibly to calf thymus DNA. Nonetheless, only ca. 20% of the Pt on the surface of the UCNPs was in the Pt(IV) oxidation state, the rest was Pt(II), indicating chemical reduction of the diiodido Pt(IV) prodrug by the UCNPs. Cytotoxicity studies with the various UCNP Pt conjugates and constructs, tested on human leukemia HL60 cells in culture, indicated a substantial increase in cytotoxicity when modified UCNPs were combined with five rounds of 30 min irradiation with NIR compared to dark controls, but NIR alone also had a significant cytotoxic effect at this duration.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0dfdb5872166e37c8e8fee73ef76127cTest
https://publications.cnr.it/doc/359889Test

المؤلفون: Frank Totzke, Claudia Götz, Marc Le Borgne, Claas Hundsdörfer, Patrick J. Bednarski, Joachim Jose, Janina Hamberger, Hans-Jörg Hemmerling

المصدر: Biochemical and Biophysical Research Communications. 424:71-75

مصطلحات موضوعية: Indoles, Stereochemistry, Biophysics, Antineoplastic Agents, Biology, Biochemistry, Receptor tyrosine kinase, Inhibitory Concentration 50, Cell Line, Tumor, Indoloquinones, Protein kinase CK2, medicine, Humans, Indolequinones, Casein Kinase II, Protein kinase A, Protein Kinase Inhibitors, Molecular Biology, Cancer, AMPK, Cell Biology, medicine.disease, Indenes, Cell culture, biology.protein, Cancer cell lines

الوصف: We previously reported indeno[1,2- b ]indoles as a novel class of potent inhibitors of the human protein kinase CK2. In the present study we prepared two novel quinoid derivatives, the indeno[1,2- b ]indoloquinones 6b and 6c , and demonstrated inhibition of the human CK2 by the compounds. Furthermore, we showed substantial antiproliferative activity of both compounds towards a broad panel of human cancer cell lines in the low micromolar range. Whereas the earlier indeno[1,2- b ]indoles have been shown to be selective for CK2, the indeno[1,2- b ]indoloquinones 6b and 6c also inhibited the AMPK activated protein kinase ARK5, potentially contributing to the anti-cancer effects of the compounds. In addition, with compound 6b we found a very potent inhibitor of the leukemia-associated receptor tyrosine kinase FLT3, with an IC 50 of 0.18 μM.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a7b65de90d8c668e58634db961b68760Test
https://doi.org/10.1016Test/j.bbrc.2012.06.068

المؤلفون: Antonio Donaire, Alicia Buceta, Gorakh S. Yellol, Christoph Janiak, Piotr Szumlas, Jyoti G. Yellol, Sergio A. Pérez, José Ruiz, Arturo Espinosa, Patrick J. Bednarski, Gamall Makhloufi

المصدر: Journal of medicinal chemistry. 58(18)

مصطلحات موضوعية: Models, Molecular, Benzimidazole, Stereochemistry, chemistry.chemical_element, Neovascularization, Physiologic, Angiogenesis Inhibitors, Antineoplastic Agents, Apoptosis, Ring (chemistry), Crystallography, X-Ray, Iridium, Ruthenium, chemistry.chemical_compound, Hydrolysis, Mice, Structure-Activity Relationship, Coordination Complexes, Cell Line, Tumor, Drug Discovery, Human Umbilical Vein Endothelial Cells, Molecule, Structure–activity relationship, Animals, Humans, Chelation, Serum Albumin, Molecular Structure, Caspase 3, Cell Cycle Checkpoints, 3. Good health, Enzyme Activation, chemistry, Drug Resistance, Neoplasm, Molecular Medicine, Benzimidazoles, Cisplatin, Drug Screening Assays, Antitumor, Reactive Oxygen Species, Hydrophobic and Hydrophilic Interactions

الوصف: A series of novel C,N-cyclometalated benzimidazole ruthenium(II) and iridium(III) complexes of the types [(η(6)-p-cymene)RuCl(κ(2)-N,C-L)] and [(η(5)-C5Me5)IrCl(κ(2)-N,C-L)] (HL = methyl 1-butyl-2-arylbenzimidazolecarboxylate) with varying substituents (H, Me, F, CF3, MeO, NO2, and Ph) in the R4 position of the phenyl ring of 2-phenylbenzimidazole chelating ligand of the ruthenium (3a-g) and iridium complexes (4a-g) have been prepared. The cytotoxic activity of the new ruthenium(II) and iridium(III) compounds has been evaluated in a panel of cell lines (A2780, A2780cisR, A427, 5637, LCLC, SISO, and HT29) in order to investigate structure-activity relationships. Phenyl substitution at the R4 position shows increased potency in both Ru and Ir complexes (3g and 4g, respectively) as compared to their parent compounds (3a and 4a) in all cell lines. In general, ruthenium complexes are more active than the corresponding iridium complexes. The new ruthenium and iridium compounds increased caspase-3 activity in A2780 cells, as shown for 3a,d and 4a,d. Compound 4g is able to increase the production of ROS in A2780 cells. Furthermore, all the new compounds are able to overcome the cisplatin resistance in A2780cisR cells. In addition, some of the metal complexes effectively inhibit angiogenesis in the human umbilical vein endothelial cell line EA.hy926 at 0.5 μM, the ruthenium derivatives 3g (Ph) and 3d (CF3) being the best performers. QC calculations performed on some ruthenium model complexes showed only moderate or slight electron depletion at the phenyl ring of the C,N-cyclometalated ligand and the chlorine atom on increasing the electron withdrawing effect of the R substituent.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::400275ebd8f51af862ca1e60cf781b8dTest
https://pubmed.ncbi.nlm.nih.gov/26313136Test

المؤلفون: Anja Bodtke, Maria Gdaniec, Patrick J. Bednarski, Ulrike Lindequist, Magdalena Buczkowska

المصدر: Archiv der Pharmazie. 344:605-616

مصطلحات موضوعية: Models, Molecular, Stereochemistry, Carboxylic Acids, Pharmaceutical Science, chemistry.chemical_element, Antineoplastic Agents, Microbial Sensitivity Tests, Medicinal chemistry, High-performance liquid chromatography, Coordination complex, Metal, chemistry.chemical_compound, Anti-Infective Agents, Cell Line, Tumor, Drug Discovery, Organometallic Compounds, Acids, Heterocyclic, Humans, Chelation, Carboxylate, Chelating Agents, Platinum, chemistry.chemical_classification, Ligand, Cobalt, Nitrogen, Zinc, chemistry, Metals, visual_art, X-ray crystallography, visual_art.visual_art_medium, Copper

الوصف: A series of Cu(II), Co(II), Pt(II) and Zn(II) coordination compounds has been prepared by the reaction of the metal chlorides with pyrazine-2-carboxylic acid, pyridine-2-carboxylic acid, imidazole-4-carboxylic acid, benzimidazole-2-carboxylic acid and 1-methylimidazole-2-carboxylic acid. The complexes were characterized by IR, UV-VIS, elemental analysis, and some by (1) H-NMR, X-ray crystallography, HPLC and LC/MS spectroscopy. All complexes consist of a 2:1 ratio of ligand to metal ion. IR and X-ray crystallography show that coordination is through the nitrogen and carboxylate oxygen donor atoms of the ligand to form chelating rings. DFT calculations predict that the trans-coordinated isomers are thermodynamically more stable than their cis-forms. Only one of five complexes studied by X-ray crystallography, Cu(II) complex of 1-methylimidazole-2-carboxylic acid showed a cis-configured metal ion center. HPLC analysis indicated that Pt(II) complex of 1-methylimidazole-2-carboxylic acid is dominated (>90%) by the trans-configured complex. All other complexes showed one isomer, presumably the trans-form. The cytotoxic activity was investigated in human cancer cell lines in vitro; only the Pt(II) complexes were active. The antimicrobial activity against four bacterial strains and one fungi was estimated by the MIC method and best results were found amongst the Co(II) complexes. These results indicate that trans-coordinated bischelating N,O-heterocyclic carboxylates of Pt(II) are an interesting new class of potential antitumor agents.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::41af9f7456b45a5aaffe59341f27ef46Test
https://doi.org/10.1002/ardp.201100101Test

المؤلفون: Renate Grünert, Andrea Eick, Patrick J. Bednarski, Klaus Weisz, Fanny Riechert-Krause

المصدر: Bioorganic & Medicinal Chemistry Letters. 21:2380-2383

مصطلحات موضوعية: Circular dichroism, Indoles, Tertiary amine, Base pair, Stereochemistry, medicine.drug_class, Clinical Biochemistry, Intercalation (chemistry), Pharmaceutical Science, Antineoplastic Agents, Carboxamide, Biochemistry, chemistry.chemical_compound, Cell Line, Tumor, Neoplasms, Drug Discovery, medicine, Humans, Transition Temperature, Molecular Biology, Chemistry, Circular Dichroism, Organic Chemistry, Biological activity, DNA, Intercalating Agents, Spectrometry, Fluorescence, Duplex (building), Quinolines, Molecular Medicine, Drug Screening Assays, Antitumor

الوصف: Phenyl-substituted indoloquinolines were studied for their biological activity and their DNA binding affinity. Water-soluble aminoalkyl derivatives were prepared and have shown significant in vitro anticancer activity. Unlike previous reports on the potential role of duplex DNA as target for various indoloquinoline based drugs, duplex UV melting experiments and fluorescence titrations suggest only weak and moderately strong binding of the phenyl-substituted indoloquinolines at 120 mM and 20 mM Na+ concentrations, respectively. Binding is suggested by ethidium displacement and circular dichroism experiments to be associated with drug intercalation between base pairs.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::50e06d4c5871f554801069920c8df441Test
https://doi.org/10.1016Test/j.bmcl.2011.02.088

المؤلفون: Gerhard Hamilton, Matthias Tacke, Ulrike Olszewski, Patrick J. Bednarski, Megan Hogan, Robert Zeillinger, James Claffey

المصدر: Investigational New Drugs. 29:607-614

مصطلحات موضوعية: Cell cycle checkpoint, DNA damage, Down-Regulation, Antineoplastic Agents, Stathmin, Cell Line, Tumor, Organometallic Compounds, medicine, Humans, Pharmacology (medical), Cell Proliferation, Platinum, Pharmacology, Cisplatin, biology, Genome, Human, Cell growth, Gene Expression Profiling, Topoisomerase, Cell Cycle, Cell cycle, Molecular biology, Up-Regulation, Gene Expression Regulation, Neoplastic, Oncology, Drug Resistance, Neoplasm, Cell culture, biology.protein, Drug Screening Assays, Antitumor, medicine.drug

الوصف: Titanocenes constitute a class of metal-based anticancer agents that seem to display a mode of action distinct from that of platinum complexes and to be more tolerable with a differing spectrum of activity. In the present study, titanocene C (bis-(N,N-dimethylamino-2(N-methylpyrrolyl)-methyl-cyclopentadienyl) titanium(IV) dichloride) was shown to exhibit antiproliferative activity against human tumor cell lines with a mean IC₅₀ value of 48.3 ± 32.5 µM. In particular, high activity was found against small cell lung cancer (SCLC) cell lines with a profile different from cisplatin. Titanocene C induced cell cycle arrest at the G1/0-S interphase. Cross-resistance to either cisplatin or oxoplatin, respectively, was low for titanocene C and absent for titanocene Y in variant HL-60 cell lines. Alterations in gene expression of NCI-H526 SCLC cells induced by titanocene C were investigated using genome-wide expression arrays. Downregulation was found for genes coding for topoisomerases I and IIα, histones of the HIST1H4 cluster, enzymes involved in glycolysis, components of the cytoskeleton and vesicular transport, among others. In contrast, expression of genes involved in apoptosis, stress response, particularly members of the metallothionein gene cluster 1, DNA damage and growth factors was upregulated following exposure to titanocene C. Approximately 50% of those genes downregulated by titanocene C and cisplatin were concordant, including the previously identified markers of cisplatin-sensitivity, tubulin and stathmin, indicating partial overlap of the pathways affected by these metal complexes. The present findings point helicases/topoisomerases and HIST1H4 core histones out as targets of titanocene C and metallothioneins as putative main effectors of drug resistance.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ca82d51beb483308bd1717ae58dd0392Test
https://doi.org/10.1007/s10637-010-9395-5Test