RESUMO
BACKGROUND: Hepatocellular carcinoma is one of the most common malignancies and leading cancer-associated deaths worldwide. Ozone has been proposed as a promising therapeutic agent in the treatment of various disorders. PURPOSE: The purpose of this paper is to assess the potential anticancer effects of the ozone on liver cancer cells. METHOD: The liver cancer cell line of bel7402 and SMMC7721 was used in this study. Proliferation was evaluated using the CCK-8 and the colony formation assay. Wond healing assay and transwell assay without Matrigel were used to evaluate their migration ability. Flow cytometry was used for cell cycle analysis and reactive oxygen species (ROS) determination. Glutathione detection kit was used for measurement of glutathione level. Protein expression was estimated by western blot analysis. RESULTS: Ozone treatment inhibited liver cancer cell proliferation, colony formation. Ozone induced G2/M phase cell cycle arrest, which could be elucidated by the change of protein levels of p53, p21, Cyclin D1, cyclin B1, cdc2, and CDK4. We also found that ozone treatment inhibited migration ability by inhibiting EMT-relating protein. Ozone also induced ROS accumulation and decreased glutathione level decreased, which contributed to the inactivation of the PI3K/AKT/NF-κB pathway. Finally, we found that pre-treatment of liver cancer cells with N-acetylcysteine resisted ozone-induced effects. CONCLUSIONS: Ozone restrains the proliferation and migration potential and EMT process of liver cancer cells via ROS accumulation and PI3K/AKT/NF-κB suppression.
Assuntos
Carcinoma Hepatocelular/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Ozônio/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Carcinoma Hepatocelular/patologia , Proteínas de Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Neoplasias Hepáticas/patologia , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ensaio Tumoral de Célula-TroncoRESUMO
Colorectal cancer (CRC) is one type of cancer with high morbidity and mortality worldwide. Photodynamic therapy (PDT), a promising new therapeutic approach for cancer, induces tumor damage through photosensitizer-mediated oxidative cytotoxicity. Hypericin is a powerful photosensitizer with pronounced tumor-localizing properties. In this study, we investigated the phototoxic effects of hypericin-mediated PDT (HYP-PDT) in HCT116 and SW620 cells. We validated that HYP-PDT inhibited cell proliferation, triggered intracellular reactive oxygen species generation, induced S phase cell cycle arrest and apoptosis of HCT116 and SW620 cells. Mechanistically, the results of western blot showed that HYP-PDT downregulated CDK2 expression through decreasing the CDC25A protein, which resulted in the decrease of CDK2/Cyclin A complex. Additionally, HYP-PDT induced DNA damage as evidenced by ATM activation and upregulation of p-H2AX. Further investigation showed that HYP-PDT significantly increased Bax expression and decreased Bcl-2 expression, and then, upregulated the expression of cleaved caspase-9, cleaved caspase-3 and cleaved PARP, thereby inducing apoptosis in HCT116 and SW620 cells. In conclusion, our results indicated that the CDC25A/CDK2/Cyclin A pathway and the mitochondrial apoptosis pathway were involved in HYP-PDT induced S phase cell cycle arrest and apoptosis in colorectal cancer cells, which shows HYP could be a probable candidate used for treating colorectal cancer.
Assuntos
Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Neoplasias Colorretais/terapia , Perileno/análogos & derivados , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Fase S/efeitos dos fármacos , Antracenos , Proteínas de Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA , Regulação para Baixo/efeitos dos fármacos , Humanos , Perileno/farmacologia , Perileno/uso terapêutico , Fármacos Fotossensibilizantes/farmacologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Mammalian nuclear distribution genes encode proteins with essential roles in neuronal migration and brain formation during embryogenesis. The implication of human nuclear distribution genes, namely nudC and NDE1 (Nuclear Distribution Element 1)/NDEL1 (Nuclear Distribution Element-Like 1), in psychiatric disorders including schizophrenia and bipolar disorder, has been recently described. The partial loss of NDEL1 expression results in neuronal migration defects, while ndel1 null knockout (KO) leads to early embryonic lethality in mice. On the other hand, loss-of-function of the orthologs of nuclear distribution element genes (nud) in Caenorhabditis elegans renders viable worms and influences behavioral endophenotypes associated with dopaminergic and serotoninergic pathways. In the present work, we evaluated the role of nud genes in monoamine levels at baseline and after the treatment with typical or atypical antipsychotics. Dopamine, serotonin and octopamine levels were significantly lower in homozygous loss-of-function mutant worms KO for nud genes compared with wild-type (WT) C. elegans at baseline. While treatment with antipsychotics determined significant differences in monoamine levels in WT, the nud KO mutant worms appear to respond differently to the treatment. According to the best of our knowledge, we are the first to report the influence of nud genes in the monoamine levels changes in response to antipsychotic drugs, ultimately placing the nuclear distribution genes family at the cornerstone of pathways involved in the modulation of monoamines in response to different classes of antipsychotic drugs.
Assuntos
Antipsicóticos/farmacologia , Monoaminas Biogênicas/metabolismo , Encéfalo/efeitos dos fármacos , Proteínas de Transporte/efeitos dos fármacos , Mutação/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/efeitos dos fármacos , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Proteínas Associadas aos Microtúbulos/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/metabolismoRESUMO
Cutaneous melanoma (CM) is an extremely aggressive cancer presenting low survival and high mortality. The vast majority of patients affected by this disease does not respond or show resistance to the chemotherapeutic drugs, which makes the treatment ineffective. In this sense, the necessity for the development of new agents to assist in CM therapy is extremely important. One of the sources of great interest in this search are compounds of natural origin. Among these compounds, caffeic acid has demonstrated a broad spectrum of pharmacological activities as well as antitumor effects in some types of cancer. Therefore, the objective of this work was to investigate the possible antitumor effect of caffeic acid on the SK-Mel-28 cell line, human CM cells. Cells were cultured in flasks with culture medium containing fetal bovine serum, antibiotic, and antifungal, and maintained in ideal conditions. Cells were treated with 25 µM, 50 µM, 100 µM, 150 µM and 200 µM of caffeic acid and dacarbazine at 1 mg/mL. We verified the effect on cell viability and cell death, apoptosis, cell cycle, colony formation and gene expression of caspases. Results showed a decrease in cell viability, cell death induction by apoptosis, inhibition of colony formation, modulation of cell cycle and alterations in gene expression of caspases after caffeic acid treatment. These results suggest an antitumor effect of the compound on SK-Mel-28 cells. This study provides original information on mechanisms by which caffeic acid may play a key role in preventing tumor progression in human melanoma cells.
Assuntos
Ácidos Cafeicos/farmacologia , Melanoma/tratamento farmacológico , Adulto , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ácidos Cafeicos/metabolismo , Caspases/efeitos dos fármacos , Caspases/genética , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/genética , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dacarbazina/farmacologia , Feminino , Voluntários Saudáveis , Humanos , Masculino , Melanoma/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Melanoma Maligno CutâneoRESUMO
Simultaneous use of cisplatin (CIS) and gemcitabine (GEN) for treating bladder cancer has increased because of their complementary effects. However, the molecular mechanisms underlying the activities of these two antineoplastic drugs are not fully known. Here, molecular biology techniques and microscopy were used to investigate transcriptomic and morphological changes in low and high-grade urinary bladder transitional carcinoma cell lines [RT4 - wild type TP53; 5637 - two TP53 mutations, one in codon 72 (Arg-Pro) and other in codon 280 (Arg-Thr) and T24 - in-frame deletion of tyrosine 126 in the TP53 allele] simultaneously treated with CIS/GEN. Gene expression profile was evaluated by PCR arrays; cell morphology by scanning and transmission electron microscopy, and apoptosis was analyzed using fluorescent dye. Results showed concomitantly upregulation of CDKN2B (G1/S transition), GADD45A (DNA repair and apoptosis) and SERTAD1 (regulation of transcription) gene, increased number of nuclear chamfers and apoptotic cells, and reduced number of microfilaments, organelles and in the size of the nucleus in 5637 and T24 cells after simultaneous treatment with CIS/GEN. In conclusion, independently of the TP53 mutation status and tumor grade, CIS/GEN induced gene modulation accompanied by changes in cell morphologies, which confirm the antiproliferative activity of the treatment protocol. These findings help to understand the pathways modulated by these antineoplastic agents and may provide insights for anti-cancer chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma de Células de Transição/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias da Bexiga Urinária/patologia , Apoptose/efeitos dos fármacos , Carcinoma de Células de Transição/metabolismo , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/biossíntese , Proteínas de Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cisplatino/farmacologia , Inibidor de Quinase Dependente de Ciclina p15/biossíntese , Inibidor de Quinase Dependente de Ciclina p15/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Humanos , Mutação , Proteínas Nucleares/biossíntese , Proteínas Nucleares/efeitos dos fármacos , Transativadores/biossíntese , Transativadores/efeitos dos fármacos , Fatores de Transcrição , Proteína Supressora de Tumor p53/genética , Regulação para Cima , Neoplasias da Bexiga Urinária/metabolismo , GencitabinaRESUMO
The effects of thallium [Tl(I) and Tl(III)] on the PC12 cell cycle were evaluated without (EGF(-)) or with (EGF(+)) media supplementation with epidermal growth factor (EGF). The following markers of cell-cycle phases were analyzed: cyclin D1 (G1 ); E2F-1, cyclin E and cytosolic p21 (G1 âS transition); nuclear PCNA and cyclin A (S); and cyclin B1 (G2). The amount of cells in each phase and the activation of the signaling cascade triggered by EGF were also analyzed. Tl(I) and Tl(III) (5-100 µM) caused dissimilar effects on PC12 cell proliferation. In EGF(-) cells, Tl(I) increased the expression of G1 âS transition markers and nuclear PCNA, without affecting cyclin A or cyclin B1. In addition to those, cyclin B1 was also increased in EGF(+) cells. In EGF(-) cells, Tl(III) increased the expression of cyclin D1, all the G1âS and S phase markers and cyclin B1. In EGF(+) cells, Tl(III) increased cyclin D1 expression and decreased all the markers of G1 âS transition and the S phase. Even when these cations did not induce the activation of EGF receptor (EGFR) in EGF(-) cells, they promoted the phosphorylation of ERK1/2 and Akt. In the presence of EGF, the cations anticipated EGFR phosphorylation without affecting the kinetics of EGF-dependent ERK1/2 and Akt phosphorylation. Altogether, results indicate that Tl(I) promoted cell proliferation in both EGF(-) and EGF(+) cells. In contrast, Tl(III) promoted the proliferation of EGF(-) cells but delayed it in EGF(+) cells, which may be related to the toxic effects of this cation in PC12 cells.
Assuntos
Ciclo Celular/efeitos dos fármacos , Ciclinas/efeitos dos fármacos , Fator de Crescimento Epidérmico/efeitos dos fármacos , Titânio/toxicidade , Animais , Cátions , Proteínas de Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/genética , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/efeitos dos fármacos , Receptores ErbB/genética , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Oncogênica v-akt/biossíntese , Proteína Oncogênica v-akt/genética , Oxirredução , Células PC12 , Fosforilação , Ratos , Transdução de Sinais/efeitos dos fármacosRESUMO
MP [4-(3',3'-dimethylallyloxy)-5-methyl-6-methoxyphthalide] was obtained from liquid culture of Pestalotiopsis photiniae isolated from the Chinese Podocarpaceae plant Podocarpus macrophyllus. MP significantly inhibited the proliferation of HeLa tumor cell lines. After treatment with MP, characteristic apoptotic features such as DNA fragmentation and chromatin condensation were observed in DAPI-stained HeLa cells. Flow cytometry showed that MP induced G1 cell cycle arrest and apoptosis in a dose-dependent manner. Western blotting and real-time reverse transcription-polymerase chain reaction were used to investigate protein and mRNA expression. MP caused significant cell cycle arrest by upregulating the cyclin-dependent kinase inhibitor p27(KIP1) protein and p21(CIP1) mRNA levels in HeLa cells. The expression of p73 protein was increased after treatment with various MP concentrations. mRNA expression of the cell cycle-related genes, p21(CIP1), p16(INK4a) and Gadd45α, was significantly upregulated and mRNA levels demonstrated significantly increased translation of p73, JunB, FKHR, and Bim. The results indicate that MP may be a potential treatment for cervical cancer.
Assuntos
Apoptose/efeitos dos fármacos , Benzofuranos/administração & dosagem , Endófitos/química , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Xylariales/química , Proteínas Reguladoras de Apoptose/genética , Benzofuranos/isolamento & purificação , Proteínas de Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cycadopsida , Inibidor de Quinase Dependente de Ciclina p21/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p27/efeitos dos fármacos , Proteínas de Ligação a DNA/efeitos dos fármacos , Citometria de Fluxo , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/efeitos dos fármacos , Genes p16/efeitos dos fármacos , Células HeLa , Humanos , Proteínas Nucleares/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Transcrição/efeitos dos fármacos , Transcrição Gênica , Proteína Tumoral p73 , Proteínas Supressoras de Tumor/efeitos dos fármacosRESUMO
MP [4-(3′,3′-dimethylallyloxy)-5-methyl-6-methoxyphthalide] was obtained from liquid culture of Pestalotiopsis photiniae isolated from the Chinese Podocarpaceae plant Podocarpus macrophyllus. MP significantly inhibited the proliferation of HeLa tumor cell lines. After treatment with MP, characteristic apoptotic features such as DNA fragmentation and chromatin condensation were observed in DAPI-stained HeLa cells. Flow cytometry showed that MP induced G1 cell cycle arrest and apoptosis in a dose-dependent manner. Western blotting and real-time reverse transcription-polymerase chain reaction were used to investigate protein and mRNA expression. MP caused significant cell cycle arrest by upregulating the cyclin-dependent kinase inhibitor p27KIP1 protein and p21CIP1 mRNA levels in HeLa cells. The expression of p73 protein was increased after treatment with various MP concentrations. mRNA expression of the cell cycle-related genes, p21CIP1 , p16INK4a and Gadd45α, was significantly upregulated and mRNA levels demonstrated significantly increased translation of p73, JunB, FKHR, and Bim. The results indicate that MP may be a potential treatment for cervical cancer.
Assuntos
Humanos , Apoptose/efeitos dos fármacos , Benzofuranos/administração & dosagem , Endófitos/química , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Xylariales/química , Proteínas Reguladoras de Apoptose/genética , Benzofuranos/isolamento & purificação , Proteínas de Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , /efeitos dos fármacos , /efeitos dos fármacos , Proteínas de Ligação a DNA/efeitos dos fármacos , Citometria de Fluxo , Fatores de Transcrição Forkhead/efeitos dos fármacos , Cycadopsida , /efeitos dos fármacos , Células HeLa , Proteínas Nucleares/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real , Transcrição Gênica , Fatores de Transcrição/efeitos dos fármacos , Proteínas Supressoras de Tumor/efeitos dos fármacosRESUMO
The purpose of this study was to evaluate mammary gland histomorphometry and proliferation rate and apoptosis of thyroxine-treated rats by CDC-47 and caspase-3 immunoexpression. The development of thyroxine-treated rats offspring was also evaluated. Thirty-six female rats were used, distributed in two groups, treated and non-treated with thyroxine. After 60 days of treatment, with thyroxine, rats were mated. Six animals/group were sacrificed on the 2nd and 21st days of lactation and on the 5th day after weaning. A significant difference was observed between groups only on the 5th day after weaning. Thyroxine treatment increased apoptosis rate, which was characterized by a higher caspase-3 expression in mammary epithelial cells. Thyroxine-treated mothers presented changed behavior, but there was no significant difference regarding taking care of offspring, as for cleaning offspring and keeping them warm. Taking into account sex and size of offspring, those from control and thyroxine-treated mothers presented no significant difference of weight and weaning. In conclusion, administering low doses of thyroxine increases apoptosis rate, which is characterized by the increased caspase-3 immunoexpression in mammary epithelial cells 5 days after weaning. But does not affect proliferation rate and development of thyroxine-treated rats offspring.
Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Lactação/efeitos dos fármacos , Glândulas Mamárias Animais/efeitos dos fármacos , Tiroxina/farmacologia , Desmame , Animais , Aleitamento Materno , Estudos de Casos e Controles , Caspase 3/efeitos dos fármacos , Caspase 3/metabolismo , Proteínas de Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Modelos Animais de Doenças , Feminino , Masculino , Glândulas Mamárias Animais/patologia , Comportamento Materno/efeitos dos fármacos , Comportamento Materno/psicologia , Gravidez , Ratos , Ratos Wistar , Tiroxina/administração & dosagemRESUMO
O objetivo deste estudo foi avaliar a histomorfometria e a taxa de proliferação e apoptose da glândula mamária de ratas tratadas com tiroxina pela imuno-expressão de CDC-47 e caspase-3, respectivamente. Também foi avaliado o desenvolvimento dos filhotes de ratas tratadas com tiroxina. Foram utilizadas 36 ratas distribuídas em dois grupos, tratado com tiroxina e controle. Após 60 dias de tratamento com tiroxina, as ratas foram acasaladas. Seis animais/grupo foram sacrificados no 2° e 21° dias de lactação e no 5° dia após o desmame. Houve diferença significativa entre grupos apenas no quinto dia após o desmame. O tratamento com tiroxina aumentou a taxa de apoptose caracterizada pela maior expressão de caspase-3 nas células do epitélio mamário. As mães tratadas com tiroxina apresentaram comportamento alterado, mas não houve diferença significativa no que se refere aos cuidados com o filhote quanto a higienização e aquecimento. Levando-se em consideração o sexo e o tamanho da ninhada, os filhotes das ratas tratadas com tiroxina e controle não apresentaram diferença significativa de peso ao desmame. Conclui-se que a administração de baixas doses de tiroxina aumenta a taxa de apoptose, caracterizada pelo aumento da expressão de caspase-3 no epitélio mamário cinco dias após o desmame, mas não altera a taxa de proliferação celular e o comportamento materno.
The purpose of this study was to evaluate mammary gland histomorphometry and proliferation rate and apoptosis of thyroxine-treated rats by CDC-47 and caspase-3 immunoexpression. The development of thyroxine-treated rats offspring was also evaluated. Thirty-six female rats were used, distributed in two groups, treated and non-treated with thyroxine. After 60 days of treatment, with thyroxine, rats were mated. Six animals/group were sacrificed on the 2nd and 21st days of lactation and on the 5th day after weaning. A significant difference was observed between groups only on the 5th day after weaning. Thyroxine treatment increased apoptosis rate, which was characterized by a higher caspase-3 expression in mammary epithelial cells. Thyroxine-treated mothers presented changed behavior, but there was no significant difference regarding taking care of offspring, as for cleaning offspring and keeping them warm. Taking into account sex and size of offspring, those from control and thyroxine-treated mothers presented no significant difference of weight and weaning. In conclusion, administering low doses of thyroxine increases apoptosis rate, which is characterized by the increased caspase-3 immunoexpression in mammary epithelial cells 5 days after weaning. But does not affect proliferation rate and development of thyroxine-treated rats offspring.
Assuntos
Animais , Feminino , Masculino , Gravidez , Ratos , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Lactação/efeitos dos fármacos , Glândulas Mamárias Animais/efeitos dos fármacos , Tiroxina/farmacologia , Desmame , Aleitamento Materno , Estudos de Casos e Controles , /efeitos dos fármacos , /metabolismo , Proteínas de Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Modelos Animais de Doenças , Glândulas Mamárias Animais/patologia , Comportamento Materno/efeitos dos fármacos , Comportamento Materno/psicologia , Ratos Wistar , Tiroxina/administração & dosagemRESUMO
BACKGROUND: Prognosis for non-small cell lung cancer (NSCLC) patients is very poor. Prediction of the response to treatment in individual patients may be possible using molecular biological alterations such as clinical biomarkers. We investigated the predictive value of apoptosis and cell cycle regulator proteins for neoadjuvant chemotherapy response in stage IIIA/IIIB NSCLC patients. METHODS: We evaluated p53, bcl-2, p21WAF1/CIP1, p27Kip1, and Ki67 immunohistochemical expression and apoptotic index in mediastinal lymph node metastases from 23 IIIA and 10 IIIB NSCLC patients before treatment with neoadjuvant platinum-based chemotherapy. Univariate analysis was performed to evaluate the relationship between protein expression and survival or time to progression (TTP). RESULTS: Median follow-up was 25 months (range, 4-112), median TTP was 11 months (range, 0-112), and median overall survival was 22 months (range, 4-112). Of 32 assessable patients, 18 (56%) had stable disease, 12 (38%) had a PR, and two (6%) had progressive disease. Of the 22 patients assessable for pN2 following chemotherapy, 16 (77%) were positive. Univariate analysis showed that shorter TTP correlated with progressive disease (p = 0.000), positive pN2 after chemotherapy (p = 0.026), high Ki67 (p = 0.022), and high p21WAF1/CIP1 (p = 0.038). CONCLUSION: Our results suggest that in IIIA/IIIB NSCLC patients, a high level of p21WAF1 expression in mediastinal lymph node metastases before neoadjuvant platinum-based chemotherapy is associated with a poor outcome. Our results suggest that expression of p21WAF1, which plays a role in preventing apoptosis, may be significant when selecting chemotherapy for NSCLC patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proteínas de Ciclo Celular/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Análise de Variância , Apoptose/fisiologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Ciclo Celular/análise , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Probabilidade , Medição de Risco , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Proteína Supressora de Tumor p53/análise , Proteína Supressora de Tumor p53/metabolismoRESUMO
Dehydroepiandrosterone (DHEA), a steroid hormone, modified the proliferation of human umbilical vein endothelial cells in a dose-dependent manner. Its inactive sulfate ester (DHEA-S) and two of its metabolites -- estradiol and testosterone -- had no inhibitory effect at physiological concentrations. Antiproliferation was associated with arrest in the G1 phase of the cell cycle, but not with cell death, as evaluated by cleavage of poly(ADP-ribose) polymerase and exposure of phosphatidylserine. The effect was not blocked by inhibitors of androgen or estrogen receptors. DHEA diminished the levels of phosphorylated retinoblastoma protein and increased the expression of p53 and p21 mRNAs. These results show that DHEA inhibits endothelial cell proliferation by regulating cell cycle relevant proteins through a cytoplasmic steroid hormone-independent pathway.