RESUMO
The results of the study of the effect of a mononuclear dinitrosyl iron complex (DNIC7) with functional sulfur-containing ligands (NO donors) on the viability of multiple myeloma cells are presented. It was shown that DNIC7 decreased cell viability and inhibited the proliferation of multiple myeloma cells, i.e., exhibits cytotoxic properties. Fluorescent analysis showed that the DNIC7 compound decreases the level of intracellular glutathione and increases the level of reactive oxygen species in multiple myeloma cells. It is assumed that DNIC7 has a therapeutic potential for the treatment of cancer.
Assuntos
Antineoplásicos/farmacologia , Ferro/farmacologia , Mieloma Múltiplo/patologia , Óxidos de Nitrogênio/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Glioblastoma multiforme (GBL) is the most common and aggressive brain neoplasm. A standard therapeutic approach for GBL involves combination therapy consisting of surgery, radiotherapy, and chemotherapy. The latter is based on temozolomide (TMZ). However, even by applying such a radical treatment strategy, the mean patient survival time is only 14.6 months. Here we review the molecular mechanisms underlying the resistance of GBL cells to TMZ including genetic and epigenetic mechanisms. Present data regarding a role for genes and proteins MGMT, IDH1/2, YB-1, MELK, MVP/LRP, MDR1 (ABCB1), and genes encoding other ABC transporters as well as Akt3 kinase in developing resistance of GBL to TMZ are discussed. Some epigenetic regulators of resistance to TMZ such as microRNA and EZH2 are reviewed.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Dacarbazina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/tratamento farmacológico , Animais , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/metabolismo , Barreira Hematoencefálica , Encéfalo/enzimologia , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Dacarbazina/metabolismo , Dacarbazina/uso terapêutico , Epigênese Genética , Glioblastoma/enzimologia , Glioblastoma/genética , Glioblastoma/terapia , Humanos , TemozolomidaRESUMO
In this work the effect of RHAMM (receptor hyaluronan-mediated motility)-target peptides was investigated on the viability, apoptosis and necrosis of prostate cancer cells (PC3m-LN4). It has been established that RHAMM-target peptides inhibited on 90 % cell viability of PC3m-LN4 cells at a concentration of 10 ug / ml (2Ñ 10-7 M) for 48 h. It has shown that RHAMM-target peptides induced apoptosis and inhibited necrosis of tumor cells. RHAMM-target peptide had no effect on fibroblasts (non-tumor cells) and fibroblasts (RHAMM-/-). The studies also revealed that RHAMM-target peptides enhanced activity of caspase-3/7 in cancer cells.
Assuntos
Proliferação de Células/efeitos dos fármacos , Proteínas da Matriz Extracelular/genética , Receptores de Hialuronatos/genética , Peptídeos/administração & dosagem , Neoplasias da Próstata/genética , Apoptose/efeitos dos fármacos , Caspase 3/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Proteínas da Matriz Extracelular/administração & dosagem , Fibroblastos/efeitos dos fármacos , Humanos , Receptores de Hialuronatos/administração & dosagem , Masculino , Peptídeos/genética , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , TransfecçãoRESUMO
In this paper we investigated the effect of RHAMM-target peptides on the invasion of breast cancer cells (MDA-MB-231). Cells were plated on gelatin substrate, Cy3-fluorescein-labeled, and then simultaneously processed with RHAMM-target peptides. Invasion of the cells was assessed by quantitative analysis of the area degradation of gelatin, using ImageJ software. We have found that RHAMM-target peptides inhibited the invasion of tumor cell by - 80% at a concentration of 10µg/ml (2x10â»7 M). By confocal microscopy we also showed that a population of cancer cells was heterogeneous and composed from small cells (invasive) and large cells, non-invasive cells with 4-5 nucleus in the cytoplasm. We found that treatment of cells with RHAMM-target peptides led to a decrease in the number of cells of large size and induced structural disorganization of actin and enhanced amount of stress-fibers of actin.
Assuntos
Neoplasias da Mama/metabolismo , Sistemas de Liberação de Medicamentos , Proteínas da Matriz Extracelular/química , Receptores de Hialuronatos/química , Peptídeos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Invasividade Neoplásica , Proteínas de Neoplasias/metabolismo , Peptídeos/química , Fibras de Estresse/metabolismoRESUMO
RHAMM-selective peptides in a concentration of 10 µg/ml (2×10(-7) M) inhibited the growth of MDA-MB-231 breast cancer cells over 48 h. Treatment of cancer cells with RHAMM-selective peptides induced apoptosis and necrosis and increased caspase-3 activity (by 30%).
Assuntos
Antineoplásicos/farmacologia , Proteínas da Matriz Extracelular/genética , Fibroblastos/efeitos dos fármacos , Receptores de Hialuronatos/genética , Peptídeos/farmacologia , Sequência de Aminoácidos , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Proteínas da Matriz Extracelular/antagonistas & inibidores , Proteínas da Matriz Extracelular/deficiência , Proteínas da Matriz Extracelular/metabolismo , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Receptores de Hialuronatos/metabolismo , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Necrose/induzido quimicamente , Oxazinas , Peptídeos/síntese química , XantenosRESUMO
Insulin effects of human multiple myeloma cell survival were studied on RPMI1640, RPMI8226, and IM9 lines differing by differentiation degree. The effects of exogenous insulin on tumor cell growth and survival varied. Insulin alone did not improve the viability of myeloma cells, while in combination with serum growth factors increased it. The IM9 cells with immunophenotype (CD(138+), CD(38-), CD(45+), CD(56-), CD(19+)) exhibited the highest sensitivity to serum growth factors, while RPMI1640 and RPMI8226 cells with (CD(138+), CD(38+), CD(45-), CD(56±), CD(19-)) immunophenotype were less sensitive. Studies of gene expression showed a significantly lower level of IRA mRNA expression in IM9 vs. RPMI1640 and RPMI8226 cells.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/fisiologia , Insulina/farmacologia , Mieloma Múltiplo/fisiopatologia , Linhagem Celular Tumoral , Primers do DNA/genética , Eletroforese em Gel de Ágar , Humanos , Imunofenotipagem , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sais de Tetrazólio , TiazóisRESUMO
Cytotoxic effect of doxorubicin in human multiple myeloma cell cultures RPMI 1640, RPMI 8226, and IM-9 was studied. The obtained data were compared with mRNA expression of MDR1, MRP1, BCRP, LRP genes responsible for the development of multiple drug resistance. IM-9 cells that differed from the other two cultures by the expression of surface differentiation markers and by mRNA expression of MDR1, BCRP, and LRP were most sensitive to doxorubicin. All cells expressed mRNA for only A-isoform of insulin receptor (IRA), while B-isoform (IRB) was not expressed. Insulin in a concentration of 5 µg/ml had no effect on the cytotoxic effect of doxorubicin in the studied cells.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Mieloma Múltiplo/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Expressão Gênica/efeitos dos fármacos , Humanos , Insulina/farmacologia , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas de Neoplasias/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Mensageiro/biossíntese , Receptor de Insulina/genéticaRESUMO
Coexpression of two mRNA isoforms for insulin-like growth factor-1 (IGF-1A and IGF-1B) and expression of YB-1 mRNA were analyzed in the bone marrow aspirates from 19 patients with multiple myeloma. It was shown that mRNA isoforms for IGF-1A and IGF-1B were mainly expressed in samples with hyperexpression of YB-1 mRNA, and, on the contrary, practically were not expressed (except sporadic cases) in samples with low level of YB-1 mRNA expression. Coexpression of mRNA isoforms for IGF-1A and IGF-1B were observed in 80% patients with multiple myeloma.
Assuntos
Fator de Crescimento Insulin-Like I/genética , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , RNA Mensageiro/biossíntese , Proteína 1 de Ligação a Y-Box/genética , Idoso , Feminino , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Isoformas de RNA/biossíntese , RNA Mensageiro/genéticaRESUMO
We studied the role of insulin-like growth factors 1 and 2 (IGF-1 and IGF-2) in functional differentiation of HC11 mouse mammary gland cells. It was found that both IGF-1 and IGF-2 activate the expression of milk protein ß-casein in the presence of prolactin and hydrocortisone. It was found that ß-casein expression is accompanied by cyclin D1 coexpression.
Assuntos
Caseínas/metabolismo , Células Epiteliais/metabolismo , Fator de Crescimento Insulin-Like II/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Animais , Western Blotting , Linhagem Celular , Ciclina D1/metabolismo , Células Epiteliais/efeitos dos fármacos , Hidrocortisona/farmacologia , Glândulas Mamárias Animais , Camundongos , Prolactina/farmacologiaRESUMO
Proinflammatory cytokine IL-1ß specifically stimulates caspase-3/7 in vitro in RGC-5 rat eye retinal neurons. Insulin and insulin-like growth factor-1 and their combination inhibit caspase-3/7 activation in these cells, induced by removal of the serum from culture medium and/or by IL-1ß treatment.
Assuntos
Caspase 3/metabolismo , Caspase 7/metabolismo , Fator de Crescimento Insulin-Like I/farmacologia , Insulina/farmacologia , Interleucina-1beta/farmacologia , Neurônios Retinianos/efeitos dos fármacos , Neurônios Retinianos/enzimologia , Animais , Linhagem Celular , Interleucina-6/farmacologia , Ratos , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Two independent colchicine (CLC)-resistant sublines of Rous sarcoma virus-transformed Syrian hamster fibroblasts were isolated. Each subline represented variants with 11- and 12.4-fold resistance, respectively, their 23- and 23.7-fold resistant descendants, as well as variants cultured in CLC-free medium for 10 months without loss of resistance. All variants demonstrated 'typical' multidrug resistance. The parental cells contained actin in dispersed form, as determined by rhodamine-phalloidin staining. In contrast, already in 11- and 12.4-fold resistant sublines up to 30% of cells demonstrated restored stress fibers. Cultivation in CLC-free medium leads to the accumulation of cells with a partially restored actin cytoskeleton. Putative mechanisms of up-regulation of stress fiber assembly in cells with P-glycoprotein-mediated multidrug resistance are discussed.
