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J Dermatol Sci ; 81(3): 182-91, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26775629


BACKGROUND: The tumor suppressor p53 controls DNA repair, cell cycle, apoptosis, autophagy and numerous other cellular processes. Imiquimod (IMQ), a synthetic toll-like receptor (TLR) 7 ligand for the treatment of superficial basal cell carcinoma (BCC), eliminates cancer cells by activating cell-mediated immunity and directly inducing apoptosis and autophagy in cancer cells. OBJECTIVE: To evaluate the role of p53 in IMQ-induced cell death in skin cancer cells. METHODS: The expression, phosphorylation and subcellular localization of p53 were detected by real-time PCR, luciferase reporter assay, cycloheximide chase analysis, immunoblotting and immunocytochemistry. Using BCC/KMC1 cell line as a model, the upstream signaling of p53 activation was dissected by over-expression of TLR7/8, the addition of ROS scavenger, ATM/ATR inhibitors and pan-caspase inhibitor. The role of p53 in IMQ-induced apoptosis and autophagy was assessed by genetically silencing p53 and evaluated by a DNA content assay, immunoblotting, LC3 puncta detection and acridine orange staining. RESULTS: IMQ induced p53 mRNA expression and protein accumulation, increased Ser15 phosphorylation, promoted nuclear translocation and up-regulated its target genes in skin cancer cells in a TLR7/8-independent manner. In BCC/KMC1 cells, the induction of p53 by IMQ was achieved through increased ROS production to stimulate the ATM/ATR-Chk1/Chk2 axis but was not mediated by inducing DNA damage. The pharmacological inhibition of ATM/ATR significantly suppressed IMQ-induced p53 activation and apoptosis. Silencing of p53 significantly decreased the IMQ-induced caspase cascade activation and apoptosis but enhanced autophagy. Mutant p53 skin cancer cell lines were more resistant to IMQ-induced apoptosis than wildtype p53 skin cancer cell lines. CONCLUSION: IMQ induced ROS production to stimulate ATM/ATR pathways and contributed to p53-dependent apoptosis in a skin basal cell carcinoma cell line BCC/KMC1.

Aminoquinolinas/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Basocelular/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Proteína Supressora de Tumor p53/metabolismo , Transporte Ativo do Núcleo Celular , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Autofagia/efeitos dos fármacos , Carcinoma Basocelular/genética , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/patologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica , Humanos , Imiquimode , Mutação , Fosforilação , Interferência de RNA , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Fatores de Tempo , Transfecção , Proteína Supressora de Tumor p53/genética
Opt Express ; 23(19): A1167-78, 2015 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-26406747


This study demonstrates the flexible white LED structure with high lumen efficiency and uniform optical performance for neutral white and warm white CCT. Flip-chip LEDs were attached on a polyimide substrate with copper strips as electrical and thermal conduction paths. Yellow phosphors are mixed with polydimenthysiloxane (PDMS) to provide mechanical support and flexibility. The light efficiency of this device can reach 120 lm/W and 85% of light output uniformity of the emission area can be achieved. Moreover, the optical simulation is employed to evaluate various designs of this flexible film in order to obtain uniform output. Both the pitch between the individual devices and the thickness of the phosphor film are calculated for optimization purpose. This flexible white LED with high lumen efficiency and good reliability is suitable for the large area fixture in the general lighting applications.

Biochim Biophys Acta ; 1853(10 Pt A): 2261-72, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25982393


There is a wide range of drugs and combinations under investigation and/or approved over the last decade to treat colorectal cancer (CRC), but the 5-year survival rate remains poor at stages II-IV. Therefore, new, more-efficient drugs still need to be developed that will hopefully be included in first-line therapy or overcome resistance when it appears, as part of second- or third-line treatments in the near future. In this study, we revealed that heat shock protein 90 (Hsp90) inhibitors have high therapeutic potential in CRC according to combinative analysis of NCBI's Gene Expression Omnibus (GEO) repository and chemical genomic database of Connectivity Map (CMap). We found that second generation Hsp90 inhibitor, NVP-AUY922, significantly downregulated the activities of a broad spectrum of kinases involved in regulating cell growth arrest and death of NVP-AUY922-sensitive CRC cells. To overcome NVP-AUY922-induced upregulation of survivin expression which causes drug insensitivity, we found that combining berberine (BBR), a herbal medicine with potency in inhibiting survivin expression, with NVP-AUY922 resulted in synergistic antiproliferative effects for NVP-AUY922-sensitive and -insensitive CRC cells. Furthermore, we demonstrated that treatment of NVP-AUY922-insensitive CRC cells with the combination of NVP-AUY922 and BBR caused cell growth arrest through inhibiting CDK4 expression and induction of microRNA-296-5p (miR-296-5p)-mediated suppression of Pin1-ß-catenin-cyclin D1 signaling pathway. Finally, we found that the expression level of Hsp90 in tumor tissues of CRC was positively correlated with CDK4 and Pin1 expression levels. Taken together, these results indicate that combination of NVP-AUY922 and BBR therapy can inhibit multiple oncogenic signaling pathways of CRC.

Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Berberina/farmacologia , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Isoxazóis/farmacologia , MicroRNAs/biossíntese , MicroRNAs/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Resorcinóis/farmacologia , Transdução de Sinais/genética