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1.
J Cell Physiol ; 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31663148

RESUMO

Lipoxygenases (LOXs) are a family of enzymes that can oxygenate polyunsaturated fatty acids. As a member of the family, 15-lipoxygenase-1 (15-LOX-1) specifically metabolizes arachidonic acid and linoleic acid. 15-LOX-1 can affect physiological and pathophysiological events via regulation of the protein-lipid interactome, alterations in intracellular redox state and production of lipid metabolites that are involved in the induction and resolution of inflammation. Although several studies have shown that 15-LOX-1 has an antitumorigenic role in many different cancer models, including breast cancer, the role of the protein in cancer drug resistance has not been established yet. In this study, we, for the first time, aimed to show the potential role of 15-LOX-1 in acquired doxorubicin (DOX) resistance in MCF7 and HeLa cancer cell lines. Our results show that ALOX15 was transcriptionally downregulated in DOX-resistant cells compared with their drug-sensitive counterparts. Moreover, overexpression of ALOX15 in the drug-resistant cells resulted in resensitization of those cells to DOX in a cell-dependent manner. 15-LOX-1 expression could induce apoptosis by activating PPARγ and enhance the accumulation of DOX in drug-resistant MCF7 cells by altering cellular motility properties, and membrane dynamics. However, HeLa DOX cells did not show any of these effects but were susceptible to cell death when treated with 13(S)-HODE. These results underline the role and importance of 15-LOX-1 in cancer drug resistance, and points to novel mechanisms as a therapeutic approach to overcome cancer drug resistance.

2.
Photochem Photobiol Sci ; 18(8): 2012-2022, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31282525

RESUMO

Organic-metal complexes are promising molecules for use in photodynamic therapy (PDT). The aim of this study was to investigate in vitro effects of novel Ru(ii) and Ir(iii) BODIPY complexes for PDT. These hybrid organic-metal molecules (Ru-BD and Ir-BD) have been synthesized via reactions of a BODIPY precursor (BD) with a phenanthroline unit bearing Ru(ii) (3) and novel Ir(iii) (4) compounds. The crystal structures of the new distyryl BODIPY (BD) and Ru(ii) complex (3) are also reported. The photophysical and singlet oxygen generation properties of Ru-BD and Ir-BD were investigated in comparison with unsubstituted BODIPY (BD). Moreover, Ru-BD and Ir-BD have been biologically evaluated in vitro in chronic myeloid leukemia and cervical cancer cell lines in terms of photodynamic therapy efficacy in the presence of BD control. These complexes were not toxic in the dark but red light was needed to induce cell death. These data support the fact that Ru-BD could be accepted as a valuable photosensitizer-drug for further PDT treatment.


Assuntos
Antineoplásicos/farmacologia , Compostos de Boro/farmacologia , Corantes/farmacologia , Compostos Organometálicos/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos de Boro/síntese química , Compostos de Boro/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Corantes/síntese química , Corantes/química , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Irídio/química , Irídio/farmacologia , Modelos Moleculares , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Rutênio/química , Rutênio/farmacologia , Oxigênio Singlete/análise , Oxigênio Singlete/metabolismo , Células Tumorais Cultivadas
3.
Artigo em Inglês | MEDLINE | ID: mdl-30684882

RESUMO

The synthesized and sensing capability of two novel azaindole substituted mono and distyryl BODIPY dyes against bisulfate anion were reported. Structural characterizations of the targeted compounds were conducted by using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, 1H and 13C NMR spectroscopies. Photophysical properties of the azaindole substituted BODIPY compounds were investigated employing absorption and fluorescence spectroscopies in acetonitrile solution. It was found that the final compounds 3 and 4 exhibited exclusively selective and sensitive turn-off sensor behavior on HSO4- anion. Additionally, the stoichiometry ratio of the targeted compounds to bisulfate anion was measured 0.5 by Job's method. Also, density function theory was performed to the optical response of the sensor for targeted compounds. Furthermore, the cytotoxicity of Azaindole-BODIPYs was examined against living human leukemia K562 cell lines.


Assuntos
Ânions/análise , Compostos de Boro/síntese química , Indóis/síntese química , Ácidos Sulfúricos/análise , Compostos de Boro/química , Calibragem , Sobrevivência Celular , Humanos , Indóis/química , Concentração Inibidora 50 , Células K562 , Conformação Molecular , Espectrometria de Fluorescência , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Eletricidade Estática
4.
Biomed Pharmacother ; 101: 129-136, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29482058

RESUMO

Drug resistance, a major challenge in cancer chemotherapy, is a result of several mechanistic alterations including resistance to apoptosis. Apoptosis is a well-controlled cell death mechanism which is regulated by several signaling pathways. Alterations in structure, function, and expression pattern of the proteins involved in the regulation of apoptosis have been linked to drug resistance. Programmed Cell Death 10 (PDCD10) protein is recently associated with the regulation of cell survival and apoptosis. However, the role of PDCD10 in drug resistance has not been clearly established. Here, we aimed to figure out the role of PDCD10 in resistance to anti-cancer agents in different cell lines. We found that PDCD10 expression was cell- and anti-cancer agent-specific; down-regulated in doxorubicin- and docetaxel-resistant MCF7 cells while up-regulated in doxorubicin-resistant HeLa cells. Down-regulation of PDCD10 expression by siRNA in parental MCF7 cells increased the resistance while it increased sensitivity in doxorubicin-resistant HeLa cells. Similarly, over-expression of PDCD10 in parental HeLa cells increased the resistance to doxorubicin while it re-sensitized doxorubicin-resistant MCF7 cells. Moreover, the alterations in PDCD10 expression led to changes in caspase 3/7 activity and the levels of apoptosis-related genes. Our results point out a possible dual role of PDCD10 in drug resistance for the first time in the literature and emphasize PDCD10 as a novel target for reversal of drug resistance in cancer.


Assuntos
Antineoplásicos/farmacologia , Proteínas Reguladoras de Apoptose/fisiologia , Apoptose/fisiologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Proteínas de Membrana/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células HeLa , Humanos , Células K562 , Células MCF-7
5.
Biometals ; 30(5): 629-641, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28766192

RESUMO

Iron is an essential inorganic element for various cellular events. It is directly associated with cell proliferation and growth; therefore, it is expected that iron metabolism is altered in tumor cells which usually have rapid growth rates. The studies on iron metabolism of tumor cells have shown that tumor cells necessitated higher concentrations of iron and the genes of iron uptake proteins were highly over-expressed. However, there are limited number of studies on overall iron metabolism in drug-resistant tumor cells. In this article, we evaluated the studies reporting the relationship between drug resistance and iron metabolism and the utilization of this knowledge for the reversal of drug resistance. Also, the studies on iron-related cell death mechanism, ferroptosis, and its relation to drug resistance were reviewed. We focus on the importance of iron metabolism in drug-resistant cancer cells and how alterations in iron metabolism participate in drug-resistant phenotype.


Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Quelantes de Ferro/uso terapêutico , Ferro/metabolismo , Neoplasias/tratamento farmacológico , Antígenos CD/genética , Antígenos CD/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Ferritinas/genética , Ferritinas/metabolismo , Proteína da Hemocromatose/genética , Proteína da Hemocromatose/metabolismo , Hepcidinas/genética , Hepcidinas/metabolismo , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Espécies Reativas de Oxigênio/metabolismo , Receptores da Transferrina/genética , Receptores da Transferrina/metabolismo , Transdução de Sinais
6.
Electrophoresis ; 38(8): 1201-1205, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28158905

RESUMO

Electrophoretic mobility is a physical phenomenon defining the mobility of charged particles in a solution under applied electric field. As charged biological systems, living cells including both prokaryotes and eukaryotes have been assessed in terms of electrophoretic mobility to decipher their electrochemical structure. Moreover, determination of electrophoretic mobility of living cancer cells have promoted the advance exploration of the nature of the cancer cells and separation of cancer cells from normal ones under applied electric field. However, electrophoretic mobility of drug-resistant cells has not yet been examined. In the present study, we determined the electrophoretic mobility of drug-resistant cancer cell lines for both suspension and adherent cells and compared with those of drug-sensitive counterparts. We showed that resistance to anticancer drugs alters the electrophoretic mobility in a permanent manner, even lasting without any exposure to anticancer agents for a long time period. We also studied the cellular morphologies of adherent cells where the cellular invaginations and protrusions were increased in drug-resistant adherent cells, which could be direct cause of altered surface charge and electrophoretic mobility as a result. These findings could be helpful in terms of understanding the electrophysiological and physicochemical background of drug resistance in cancer cells and developing systems to separate drug-sensitive cells from drug-resistant ones.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Eletroforese/métodos , Neoplasias/patologia , Adesão Celular , Linhagem Celular Tumoral , Forma Celular , Humanos , Propriedades de Superfície
7.
PLoS One ; 10(8): e0136423, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26295471

RESUMO

Estrogen receptor α (ERα), as a ligand-dependent transcription factor, mediates 17ß-estradiol (E2) effects. ERα is a modular protein containing a DNA binding domain (DBD) and transcription activation domains (AD) located at the amino- and carboxyl-termini. The interaction of the E2-activated ERα dimer with estrogen response elements (EREs) of genes constitutes the initial step in the ERE-dependent signaling pathway necessary for alterations of cellular features. We previously constructed monomeric transcription activators, or monotransactivators, assembled from an engineered ERE-binding module (EBM) using the ERα-DBD and constitutively active ADs from other transcription factors. Monotransactivators modulated cell proliferation by activating and repressing ERE-driven gene expressions that simulate responses observed with E2-ERα. We reasoned here that integration of potent heterologous repression domains (RDs) into EBM could generate monotransrepressors that alter ERE-bearing gene expressions and cellular proliferation in directions opposite to those observed with E2-ERα or monotransactivators. Consistent with this, monotransrepressors suppressed reporter gene expressions that emulate the ERE-dependent signaling pathway. Moreover, a model monotransrepressor regulated DNA synthesis, cell cycle progression and proliferation of recombinant adenovirus infected ER-negative cells through decreasing as well as increasing gene expressions with polar directions compared with E2-ERα or monotransactivator. Our results indicate that an 'activator' or a 'repressor' possesses both transcription activating/enhancing and repressing/decreasing abilities within a chromatin context. Offering a protein engineering platform to alter signal pathway-specific gene expressions and cell growth, our approach could also be used for the development of tools for epigenetic modifications and for clinical interventions wherein multigenic de-regulations are an issue.


Assuntos
Polaridade Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Receptor alfa de Estrogênio/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Fatores de Transcrição/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Polaridade Celular/fisiologia , Proliferação de Células/fisiologia , Receptor alfa de Estrogênio/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Engenharia Genética/métodos , Humanos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Fatores de Transcrição/genética , Ativação Transcricional/efeitos dos fármacos , Ativação Transcricional/fisiologia
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