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2.
Chem Commun (Camb) ; 56(20): 3069-3072, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32049075

RESUMO

Niacin-ligated platinum(iv)-ruthenium(ii) chimeric complexes (PtRu 1-4) have been synthesized and evaluated for their antitumor performance. Using the optimal complex, PtRu-1, we show that this water-soluble chimeric prodrug not only potently inhibits the metastasis and proliferation of tumor cells but also has an unexpectedly higher safety margin in animals compared with the traditionally-used, clinically approved drug cisplatin.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Niacina/farmacologia , Platina/farmacologia , Rutênio/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Peso Corporal/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/química , Cisplatino/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Niacina/química , Platina/química , Rutênio/química , Relação Estrutura-Atividade
3.
Inorg Chem ; 59(1): 748-758, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31808678

RESUMO

The rational design by the introduction of fluorine into a compound has achieved success in the development of organic anticancer drugs. However, the fluorine effect in metal-based anticancer complexes has rarely been reported. In this contribution, we report the synthesis, characterization, chemical reactivity, and biological activity of a series of half-sandwich zwitterionic iridium(III) complexes containing different substituents in the η5-CpR ring. The molecular structures for complexes Ir1-Ir4 and Ir7 were determined by single-crystal X-ray crystallography techniques. Notably, the asymmetrically substituted fluoro complexes Ir4 and Ir6 in solution show two conformational isomers. These complexes have sufficient stability, exhibit fluorescence emission, and show potent catalytic activity in converting NADH to NAD+. The effect of the substituents in the η5-CpR ring for these zwitterionic complexes on their anticancer activity was systematically investigated. Surprisingly, the presence of fluorinated substituents gives rise to a significant increase in the anticancer activity. The lipophilicity and cellular uptake levels of these complexes appeared to be the primary factors for their cytotoxicity in this system. A microscopic mechanism study showed that the typical complex Ir4 entered A549 cancer cells through an energy-dependent pathway and was mainly located in lysosomes. Furthermore, an increase in ROS level, apoptosis induction, and cell-cycle perturbation together contribute to the anticancer potency of these zwitterionic complexes.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Flúor/química , Irídio/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/química , Cisplatino/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Irídio/química , Modelos Moleculares , Estrutura Molecular , Espécies Reativas de Oxigênio/análise
4.
Carbohydr Polym ; 227: 115333, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31590864

RESUMO

The gold nanoparticles surface was modified by thioglycolic acid ligand and their surface was coated by the chitosan-grafted-poly(N-vinylcaprolactam) (chitosan-g-PNVCL) copolymer. The cisplatin anticancer drug was loaded into the synthesized nanocarriers and its performance was investigated for the treatment of MCF-7 breast cancer cells in vitro. The synthesized nanoparticles were characterized using FTIR, DLS, TEM, SEM, EDX and TGA analysis. The lower critical solution temperature (LCST) of PNVCL/chitosan and PNVCL/chitosan coated gold nanoparticles were found to be 38 and 39 °C, respectively. The cisplatin loading efficiency, cisplatin release from nanoparticles at different temperatures and pH values as well as the pharmacokinetic studies were examined. The maximum cisplatin release from nanoparticles was achieved at T > LCST (42 °C) and pH of 5. The Korsemeyer-Peppas model was best described the cisplatin release from nanoparticles. The maximum MCF cell death was found to be 92% using cisplatin loaded-gold/TGA/chitosan-g-PNVCL nanoparticles under an induction heating system.


Assuntos
Antineoplásicos , Caprolactama/análogos & derivados , Quitosana , Cisplatino , Ouro , Nanopartículas Metálicas , Polímeros , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Caprolactama/administração & dosagem , Caprolactama/química , Caprolactama/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Quitosana/administração & dosagem , Quitosana/química , Quitosana/farmacocinética , Cisplatino/administração & dosagem , Cisplatino/química , Cisplatino/farmacocinética , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Liberação Controlada de Fármacos , Ouro/administração & dosagem , Ouro/química , Humanos , Células MCF-7 , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/química , Polímeros/administração & dosagem , Polímeros/química , Polímeros/farmacocinética
5.
Comput Biol Chem ; 83: 107155, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31706153

RESUMO

Cisplatin ceases cell division and induces apoptosis in cancer cell lines. It is well established that cisplatin alters the expression of many genes involved in several cellular processes and pathways including transcription, p53 signaling pathway, and apoptosis. However, system-wide responses to cisplatin in breast cancer cell lines have not been studied. Therefore, we have used a network analysis approach to unveil such responses at early stages of drug treatment. To do this, we have first identified those genes that are responding to cisplatin treatment in MCF-7 cell line. Network and gene ontology analyses were then employed to uncover the molecular pathways affected by cisplatin treatment. Then the results obtained from cisplatin-treated MCF7 cell line were compared to those obtained from other cancer cell lines at comparable time points. In conclusion, we found that ADCY9, GSK3B, MAPK14, NCK1, NCOA2, PIK3CA, PIK3CB, PTK2, RHOB act as hub genes in the cisplatin-responsive regulatory network at the pro-apoptotic stages. The results could be useful in finding new drugs to target these genes in order to obtain similar responses.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Cisplatino/farmacologia , Ontologia Genética , Antineoplásicos/química , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Cisplatino/química , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Células MCF-7 , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Mapas de Interação de Proteínas , Software
6.
Chem Commun (Camb) ; 55(93): 13987-13990, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31687673

RESUMO

Polyprodrug-based delivery technique is a fast-growing and effective strategy to improve the therapeutic efficacy of small molecule drugs. We herein developed a robust mitoxantrone (MTO)-based polyprodrug nanoplatform for systemic cisplatin prodrug delivery and combination cancer therapy. Our results show that this nanoplatform can concurrently transport MTO and cisplatin to tumor cells and significantly inhibit tumor growth.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Sistemas de Liberação de Medicamentos , Mitoxantrona/farmacologia , Nanopartículas/química , Polímeros/farmacologia , Pró-Fármacos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/química , Terapia Combinada , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Mitoxantrona/química , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Imagem Óptica , Tamanho da Partícula , Polímeros/química , Pró-Fármacos/química , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo
7.
Pharm Res ; 36(12): 182, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31741089

RESUMO

PURPOSE: Combination chemotherapy is gradually receiving more attention because of its potential synergistic effect and reduced drug doses in clinical application. However, how to precisely control drug release dose and time using vehicles remains a challenge. This work developed an efficient drug delivery system to combat breast cancer, which can enhance drug effects despite reducing its concentration. METHODS: Controlled-release poly-lactic-co-glycolic acid (PLGA) scaffolds were fabricated by E-jet 3D printing to deliver doxorubicin (DOX) and cisplatin (CDDP) simultaneously. RESULTS: This drug delivery system allowed the use of a reduced drug dosage resulting in a better effect on the human breast cancer cell apoptosis and inhibiting tumor growth, compared with the effect of each drug and the two drugs administrated without PLGA scaffolds. Our study suggested that DOX-CDDP-PLGA scaffolds could efficiently destroy MDA-MB-231 cells and restrain tumor growth. CONCLUSIONS: The 3D printed PLGA scaffolds with their time-programmed drug release might be useful as a new multi-drug delivery vehicle in cancer therapy, which has a potential advantage in a long term tumor cure and prevention of tumor recurrence.


Assuntos
Antineoplásicos/química , Cisplatino/química , Doxorrubicina/química , Portadores de Fármacos/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/administração & dosagem , Cisplatino/farmacologia , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Quimioterapia Combinada/métodos , Excipientes/química , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Impressão Tridimensional
8.
Chem Biol Interact ; 314: 108841, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31586452

RESUMO

Despite the existence of multimodal therapy concepts, glioblastoma remains a tumor type with one of the worst prognoses. In particular, the poor prognosis is due to the lack of therapeutic efficacy of chemical agents and irradiation in hypoxic tumor areas. New therapeutic strategies could improve the treatment of glioblastoma. In this study, we investigated the therapeutic efficacy of a conjugate of cisplatin (DDP), a widely used chemotherapeutic agent, and betulinic acid (BA), a natural product from plane tree bark, in glioblastoma cells under different oxygen conditions. We investigated the effects of the BA-DDP conjugate κN',N''-{3-acetyloxy-BA-28-[2-(2-aminoethyl)aminoethyl]amide} dichlorido platinum(II) (APC) and its precursor 3-acetyloxy-BA-28-[2-(2-aminoethyl)aminoethyl]amide (DE9B) on cytotoxicity, cell growth, apoptosis, migration and radiosensitivity compared to BA or DDP alone under different oxygen conditions. Based on the EC50 values, the precursor DE9B exhibited the strongest cytotoxic effects of the analyzed chemotherapeutic agents. The BA-DDP conjugate APC achieved a moderate cytotoxic effect in glioma cells. Both of the newly developed agents induced cell growth delay, apoptosis and inhibition of migration. Furthermore, additive effects could be achieved in combination with irradiation. In contrast to those of BA and DDP, the cell biological effects of APC and DE9B were not influenced by the oxygen concentration. In this study, the linking of BA and DDP did not produce a compound with additive therapeutic effects on glioblastoma cell lines in vitro. Nevertheless, the results of this study suggest that the precursor DE9B is an effective BA derivative for the treatment of glioblastoma in vitro.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cisplatino/química , Complexos de Coordenação/farmacologia , Triterpenos/química , Antineoplásicos/química , Caspase 3/metabolismo , Caspase 7/metabolismo , Hipóxia Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Glioma/metabolismo , Glioma/patologia , Humanos
10.
Oncol Rep ; 42(5): 2087-2096, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31545462

RESUMO

The rate of lung cancer in tuberculosis (TB) patients is 7 to 30% higher than that in healthy individuals. Conventional chemotherapy of lung cancer shows limited efficiency due to poor tumor tissue drug accumulation and nonspecific cytotoxicity. Epidermal growth factor receptor (EGFR) is a promising target, which is overexpressed in lung carcinomas. In the present study, EGFR­targeted nanoparticles were constructed and co­delivered cisplatin (CDDP) and doxorubicin (DOX) for lung cancer therapy. In the present research, EGF­PEG­DSPE was synthesized. Then, EGFR­targeted lipid polymeric nanoparticles (LPNs) were fabricated, which consisted of a CDDP­loaded hybrophobic polymeric core, a DOX­loaded phospholipid layer, and an outer layer of EGF­PEG­DSPE ligand. The particle size, ζ potential, stability, release behavior of LPNs were characterized. The antitumor ability of LPNs were assessed in vitro and in vivo. EGFR­targeted LPNs loaded with CDDP and DOX (EGF C/D LPNs) had a size of 141.6 nm, and could encapsulate over 80% of feed drugs. Dual drug­loaded LPNs showed synergistic effects with a combination index (CI) of 0.57. EGF C/D LPNs showed the smallest tumor volume (253 mm3), with a tumor inhibition ratio of 74.5%. In summary, EGF C/D LPNs were stable and released the drugs in a sustained manner. In vitro and in vivo studies revealed that EGF C/D LPNs exhibited improved anticancer activity along with lower toxicity. These results indicated the best efficiency of EGF C/D LPNs for lung carcinoma therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cisplatino/administração & dosagem , Doxorrubicina/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Células A549 , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/química , Cisplatino/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacologia , Receptores ErbB/antagonistas & inibidores , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Terapia de Alvo Molecular , Nanopartículas , Tamanho da Partícula , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Int J Mol Sci ; 20(18)2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31500118

RESUMO

Cancer cells cope with high oxidative stress levels, characterized by a shift toward the oxidized form (GSSG) of glutathione (GSH) in the redox couple GSSG/2GSH. Under these conditions, the cytosolic copper chaperone Atox1, which delivers Cu(I) to the secretory pathway, gets oxidized, i.e., a disulfide bond is formed between the cysteine residues of the Cu(I)-binding CxxC motif. Switching to the covalently-linked form, sulfur atoms are not able to bind the Cu(I) ion and Atox1 cannot play an antioxidant role. Atox1 has also been implicated in the resistance to platinum chemotherapy. In the presence of excess GSH, the anticancer drug cisplatin binds to Cu(I)-Atox1 but not to the reduced apoprotein. With the aim to investigate the interaction of cisplatin with the disulfide form of the protein, we performed a structural characterization in solution and in the solid state of oxidized human Atox1 and explored its ability to bind cisplatin under conditions mimicking an oxidizing environment. Cisplatin targets a methionine residue of oxidized Atox1; however, in the presence of GSH as reducing agent, the drug binds irreversibly to the protein with ammine ligands trans to Cys12 and Cys15. The results are discussed with reference to the available literature data and a mechanism is proposed connecting platinum drug processing to redox and copper homeostasis.


Assuntos
Cisplatino/metabolismo , Glutationa/metabolismo , Chaperonas Moleculares/metabolismo , Oxirredução , Cisplatino/química , Cobre/metabolismo , Dissulfetos/química , Glutationa/química , Humanos , Metalochaperonas/metabolismo , Modelos Moleculares , Chaperonas Moleculares/química , Ligação Proteica , Conformação Proteica , Proteólise , Espécies Reativas de Oxigênio/metabolismo , Análise Espectral
12.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370253

RESUMO

Low-energy electrons (LEEs) of energies ≤30 eV are generated in large quantities by ionizing radiation. These electrons can damage DNA; particularly, they can induce the more detrimental clustered lesions in cells. This type of lesions, which are responsible for a large portion of the genotoxic stress generated by ionizing radiation, is described in the Introduction. The reactions initiated by the collisions of 0.5-30 eV electrons with oligonucleotides, duplex DNA, and DNA bound to chemotherapeutic platinum drugs are explained and reviewed in the subsequent sections. The experimental methods of LEE irradiation and DNA damage analysis are described with an emphasis on the detection of cluster lesions, which are considerably enhanced in DNA-Pt-drug complexes. Based on the energy dependence of damage yields and cross-sections, a mechanism responsible for the clustered lesions can be attributed to the capture of a single electron by the electron affinity of an excited state of a base, leading to the formation of transient anions at 6 and 10 eV. The initial capture is followed by electronic excitation of the base and dissociative attachment-at other DNA sites-of the electron reemitted from the temporary base anion. The mechanism is expected to be universal in the cellular environment and plays an important role in the formation of clustered lesions.


Assuntos
Antineoplásicos/química , DNA/efeitos da radiação , Elétrons , Radiossensibilizantes/química , Bromouracila/química , Carboplatina/química , Cisplatino/química , DNA/química , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Células Eucarióticas/química , Células Eucarióticas/efeitos da radiação , Humanos , Oligonucleotídeos/química , Oligonucleotídeos/efeitos da radiação , Oxaliplatina/química , Plasmídeos/química , Plasmídeos/efeitos da radiação , Radiação Ionizante
13.
Chemistry ; 25(53): 12275-12280, 2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31389071

RESUMO

A range of oxobis(phenyl-1,3-butanedione) vanadium(IV) complexes have been successfully synthesized from cheap starting materials and a simple and solvent-free one-pot dry-melt reaction. This direct, straightforward, fast and alternative approach to inorganic synthesis has the potential for a wide range of applications. Analytical studies confirm their successful synthesis, purity and solid-state coordination, and we report the use of such complexes as potential drug candidates for the treatment of cancer. After a 24 hour incubation of A549 lung carcinoma cells with the compounds, they reveal cytotoxicity values elevenfold greater than cisplatin and remain non-toxic towards normal cell types. Additionally, the complexes are stable over a range of physiological pH values and show the potential for interactions with bovine serum albumin.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/toxicidade , Complexos de Coordenação/síntese química , Vanádio/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Bovinos , Cisplatino/química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Humanos , Soroalbumina Bovina/química , Soroalbumina Bovina/metabolismo , Solventes
14.
Int J Pharm ; 570: 118638, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31449842

RESUMO

Osteosarcoma is the bone tumor that most commonly affects children and teenagers with low survival rate because of metastatic relapse or recurrence. Cisplatin is a first-line chemotherapy for osteosarcoma. However, severe side effects limit its use in clinic. Selenium (Se) is an anticarcinogen that can protect normal tissues from side effects of chemotherapy. In this study, nanoparticles were used to co-deliver cisplatin and Se in a synergistic combination. Se-doped and lipid-coated calcium carbonate nanoparticles loaded with cisplatin (Pt/Se@CaCO3 NPs) were prepared by a reverse microemulsion method. The NPs delivered cisplatin and Se to tumour cells at an optimal synergistic ratio of 1:1 (mol/mol) both in vitro and in an osteosarcoma xenograft model. These results demonstrate that Pt/Se@CaCO3 NPs have great prospects for the osteosarcoma therapy.


Assuntos
Carbonato de Cálcio/química , Cisplatino/química , Nanopartículas/química , Selênio/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Linhagem Celular Tumoral , Cisplatino/farmacologia , Emulsões/química , Humanos , Lipídeos/química , Camundongos , Camundongos Nus , Osteossarcoma/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
15.
Colloids Surf B Biointerfaces ; 182: 110365, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31344612

RESUMO

Stimuli-responsive polymeric nanogels have been proposed as nanocarriers of cisplatin to maximize its effect for cancer treatment. In this work, a comparative study between anionic core nanogels (ACN) and cationic core nanogels (CCN), both with PEGylated shells, has been performed. The nanogels were synthesized with different cross-linked cores: CCN with poly(N,N-diethylaminoethyl methacrylate) (PDEAEMA) and ACN with poly(2-methacryloyloxi benzoic acid) (P2MBA). Cisplatin chelate formation with carboxylic acids (ACN) or metal coordination with the amine groups (CCN) leads to a high loading of cisplatin into the nanocarriers. The nanocarriers ability to contain and modulate the supply of cisplatin was tested according to the pH of the medium, in which ACN efficiently released the drug at a typical pH value of a tumor tissue (pH = 6.8) while CCN only releases the drug at more acidic, endosome like, conditions (pH = 5). The effect of drug-free nanogels on cell lines NCI-H1437 (non-small cell lung carcinoma) was evaluated, showing biocompatibility at all concentrations studied (30-400 µg/mL) for both ACN and CCN. However, the survival percentage of the cells in contact with cisplatin-loaded nanogels were dependent on the dose, the time of contact and the type of nanogel. Cisplatin loaded CCN induced lower cell viability after 48 h of contact. Fluorescence microscopy showed a viable internalization of the CCN nanogels, this was confirmed by flow cytometry in which 37.8% of cells contained drug loaded CCNs after 30 min of contact, representing a more effective nanocarrier for cisplatin to this cell-line.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Portadores de Fármacos , Nanopartículas/química , Ânions , Antineoplásicos/química , Ácidos Carboxílicos/química , Cátions , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/química , Reagentes para Ligações Cruzadas/química , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Cinética , Metacrilatos/química , Polietilenoglicóis/química , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/patologia
16.
Artif Cells Nanomed Biotechnol ; 47(1): 3079-3086, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31352799

RESUMO

The engineering of multifunctional therapeutics in an integrated single platform is demonstrated using three-dimensional SBA-16 (S-16). 10 wt% iron oxide nanoparticles (Fe) were loaded into the cage type of cubic pores through enforced adsorption technique. Fe/S-16 is then functionalized with amine-based silane (A), polyacrylic acid (P) and cisplatin (Cp). The physicochemical textural analysis showed the formation of nano metal oxide distributions at pore walls of S-16 with magnetization of 2.39 emu/g. S-16 based nanoformulations showed high percentage of Cp adsorption (90%) and percentage cumulative release (60%). in vitro study of Fe/S-16-A-Cp showed high toxicity against breast cancer cell line MCF-7 and normal cell line Human foreskin fibroblast (HFF-1) compared to Fe/S-16 indicating cisplatin profusion inside the cells than free cisplatin. While skin fibroblast seems to be resistant to Fe/S-16-AP-Cp with very high LC50 in compare to MCF-7. This indicates the unrelease of cisplatin in skin fibroblast after Fe/S-16-AP-Cp treatment due to effective encapsulation inside the cubic pores and core blockage due to pH-sensitive polyacrylic acid. Also, these treatments resulted in morphological changes in the cells such as DNA condensation and nuclear fragmentation.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/patologia , Cisplatino/química , Cisplatino/farmacologia , Imãs/química , Dióxido de Silício/química , Resinas Acrílicas/química , Aminas/química , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/patologia , Relação Dose-Resposta a Droga , Portadores de Fármacos/química , Humanos , Células MCF-7 , Nanopartículas/química
17.
Int J Mol Sci ; 20(15)2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31357442

RESUMO

The aim of this study was to investigate the influence of the Notch1 activity level on the pharmacological interaction between cisplatin (CDDP) and two histone deacetylase inhibitors (HDIs)-valproic acid (VPA) and vorinostat (SAHA) in the triple negative breast cancer (TNBC) cells. Stable breast cancer (BC) cell lines with increased and decreased activity of Notch1 were generated using a transfection method. The type of interaction between CDDP and the HDIs was determined by isobolographic analysis of cell proliferation in MDA-MB-231 cells with differential levels of Notch1 activity in vitro. The combination of CDDP/SAHA and CDDP/VPA in the MDA-MB-231 triple negative breast cancer (TNBC) cells with increased activity of Notch1, as well as CDDP/VPA in the MDA-MB-231 cells with decreased activity of Notch1, yielded an additive interaction, whereas additivity with a tendency towards antagonism was observed for the combination of CDDP/SAHA in MDA-MB-231 cells with the decreased activity of Notch1. Our studies demonstrated that SAHA and VPA might be considered as potential therapeutic agents in combination therapy with CDDP against TNBC with altered Notch1 activity.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Receptor Notch1/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Antagonismo de Drogas , Interações de Medicamentos , Sinergismo Farmacológico , Feminino , Expressão Gênica , Inibidores de Histona Desacetilases/química , Humanos , Camundongos , Estrutura Molecular , Receptor Notch1/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Exp Oncol ; 41(2): 106-111, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31262160

RESUMO

BACKGROUND: Cisplatin (Cis-Pt) is a widely used anticancer drug but its therapeutic efficiency is limited by hemato-, cardio-, hepato-, nephro- and neurotoxicity. Complexation of Cis-Pt with C60 fullerene nanoparticle will allow to enhance the antitumor activity of the drug and to reduce its side toxic effects. AIM: To estimate the antitumor effects of С60-Cis-Pt nanocomplex in Lewis lung carcinoma (LLC) and analyze hematological toxicity in tumor-bearing mice. MATERIALS AND METHODS: Complexation of C60 fullerene and Cis-Pt molecule was studied by computer simulation. С60-Cis-Pt nanocomplex was i.p. injected to LLC-bearing mice in a total dose of 7.5 mg/kg (C60:Cis-Pt as 3.75:3.75 mg/kg). The survival of tumor-bearing mice and the relative reduction of tumor weight was recorded. Blood indices were determined using the Particle Counter PCE-210 automatic hematology analyzer. RESULTS: Computer simulation demonstrated the formation of С60-Cis-Pt nanocomplex in physiological medium and its stability due to the hydrophobic interactions. Treatment with C60-Cis-Pt nanocomplex increased survival time of LLC-bearing mice by 32%, normalized hemoglobin content (up to 100 g/l), erythrocyte and platelet count as compared to the untreated LLC-bearing mice. Tumor weight decreased by 35.5%; the mitotic index of tumor cells decreased by 78%, and apoptotic index increased by 75%. The revealed effects of the C60-Cis-Pt nanocomplex were more pronounced than the effects of Cis-Pt or C60 fullerene alone in equivalent dose. CONCLUSION: Treatment with C60-Cis-Pt nanocomplex prolonged the survival of LLC-bearing mice and reduced anemia in LLC-bearing mice.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Cisplatino/uso terapêutico , Simulação por Computador , Fulerenos/uso terapêutico , Animais , Carcinoma Pulmonar de Lewis/patologia , Linhagem Celular Tumoral , Cisplatino/química , Fulerenos/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química
19.
Emerg Microbes Infect ; 8(1): 895-908, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223062

RESUMO

The Prp8 intein is one of the most widespread eukaryotic inteins, present in important pathogenic fungi, including Cryptococcus and Aspergillus species. Because the processed Prp8 carries out essential and non-redundant cellular functions, a Prp8 intein inhibitor is a mechanistically novel antifungal agent. In this report, we demonstrated that cisplatin, an FDA-approved cancer drug, significantly arrested growth of Prp8 intein-containing fungi C. neoformans and C. gattii, but only poorly inhibited growth of intein-free Candida species. These results suggest that cisplatin arrests fungal growth through specific inhibition of the Prp8 intein. Cisplatin was also found to significantly inhibit growth of C. neoformans in a mouse model. Our results further showed that cisplatin inhibited Prp8 intein splicing in vitro in a dose-dependent manner by direct binding to the Prp8 intein. Crystal structures of the apo- and cisplatin-bound Prp8 inteins revealed that two degenerate cisplatin molecules bind at the intein active site. Mutation of the splicing-site residues led to loss of cisplatin binding, as well as impairment of intein splicing. Finally, we found that overexpression of the Prp8 intein in cryptococcal species conferred cisplatin resistance. Overall, these results indicate that the Prp8 intein is a novel antifungal target worth further investigation.


Assuntos
Antifúngicos/administração & dosagem , Cisplatino/administração & dosagem , Criptococose/microbiologia , Cryptococcus neoformans/efeitos dos fármacos , Proteínas Fúngicas/genética , Inteínas , Proteínas de Ligação a RNA/genética , Sequência de Aminoácidos , Animais , Antifúngicos/química , Cisplatino/química , Cryptococcus neoformans/genética , Cryptococcus neoformans/crescimento & desenvolvimento , Cryptococcus neoformans/metabolismo , Feminino , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/metabolismo , Alinhamento de Sequência
20.
Spectrochim Acta A Mol Biomol Spectrosc ; 220: 117102, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31146207

RESUMO

Quantum chemical analyses were performed over enrofloxacin and boron complexes. The most stable isomer of enrofloxacin was examined at M062X/6-31+G(d) level in gas phase. Structural and spectral characterizations of enrofloxacin and its complexes were performed at same level of theory. MEP maps of studied compound were calculated via ESP charges analyses. Some quantum chemical descriptors (QCDs) were calculated to determine the non-linear optical (NLO) and biological reactivity of studied molecules. Furthermore, molecular docking calculations between boron complexes and a protein (ID: 2ITN and 2ITV) were done. ADME analyses were done in the determination of the best drug candidate. As a result, complex (3) was found as the best in the NLO applications and it was found that complex (1) and (3) have similar biological reactivity in lung cancer treatment.


Assuntos
Compostos de Boro/química , Enrofloxacina/química , Antibacterianos/química , Antibacterianos/farmacocinética , Antineoplásicos/química , Antineoplásicos/farmacocinética , Compostos de Boro/farmacocinética , Cisplatino/química , Cisplatino/farmacologia , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/farmacologia , Enrofloxacina/farmacocinética , Ligações de Hidrogênio , Isomerismo , Espectroscopia de Ressonância Magnética , Conformação Molecular , Simulação de Acoplamento Molecular , Teoria Quântica , Receptores de Fatores de Crescimento do Endotélio Vascular/química , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Espectrofotometria Infravermelho , Termodinâmica , Ureia/química
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