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1.
J Investig Med High Impact Case Rep ; 12: 23247096241258076, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38818904

RESUMO

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) occurs in the jawbone and interfacing oral mucosa of patients treated with bisphosphonates. Herein, we report novel histopathological findings in the oral mucosa of a surgical specimen obtained from a 61-year-old man with BRONJ. The resected jawbone and adjacent oral mucosa were separated for histological examination. The mucosal tissue was examined using Von Kossa staining and immunohistochemical (CK5/6, p63) staining of non-decalcified paraffin sections. Pseudoepitheliomatous hyperplasia (PEH), a microscopic feature of the mucosal epithelium in BRONJ, was observed in soft tissue specimens, concomitant with inflammatory cell infiltration. Von Kossa staining revealed small fragments of necrotic bone, tens to hundreds of micrometers in size, scattered within the connective tissues; the PEH forefront contacted some of the bone fragments. Immunohistochemical staining demonstrated that occasionally, the PEH not only contacted but also encompassed the bone fragments. To our knowledge, this is the first report of presence of micro bone fragments and their association with PEH in the oral mucosa in BRONJ.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos , Mucosa Bucal , Humanos , Masculino , Pessoa de Meia-Idade , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/patologia , Mucosa Bucal/patologia , Conservadores da Densidade Óssea/efeitos adversos , Hiperplasia/patologia , Imuno-Histoquímica
2.
Diagnostics (Basel) ; 12(8)2022 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-36010185

RESUMO

Antiresorptive agent-related osteonecrosis of the jaw (ARONJ), a multifactorial disease, can drastically affect a patient's quality of life. Moreover, disease progression to severe acute inflammation can hinder treatment. Therefore, we aimed to investigate the diagnostic value of the neutrophil−lymphocyte ratio (NLR) and platelet−lymphocyte ratio (PLR) in predicting the risk of acute inflammation in patients with ARONJ. In total, 147 patients with ARONJ were enrolled between 1 January 2011 and 31 December 2019. They were divided into two groups according to their baseline NLR (high NLR vs. low NLR) or PLR (high PLR vs. low PLR) to analyze the relationship between NLR and PLR and the outcomes of acute inflammatory events. An optimal NLR cut-off value of 2.83 was identified for hospitalization for an inflammatory event. Logistic regression analysis showed that NLR > 2.83 was associated with an increased risk of hospitalization for an inflammatory event. A PLR cut-off value of 165.2 was identified for hospitalization for an inflammatory event. However, logistic regression analysis showed that PLR > 165.2 was not significantly associated with hospitalization for an inflammatory event. Our study findings suggest that the NLR has diagnostic value in predicting the risk of hospitalization for inflammatory events among patients with ARONJ.

3.
Case Rep Dent ; 2021: 9918199, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34589239

RESUMO

Chédiak-Higashi syndrome (CHS), a rare autosomal recessive disorder associated with leukocyte dysfunction, is characterised by partial skin and hair albinism, immunodeficiency, and abnormal bleeding. Furthermore, it may be associated with cognitive and neurological impairments. The long-term prognosis of patients is generally poor, and haematopoietic stem cell transplantation is a radical immunodeficiency treatment. Here, we report a case of successful oral management of an 18-year-old woman with CHS accompanied by aggressive periodontitis who underwent haematopoietic stem cell transplantation.

4.
Anticancer Res ; 39(11): 6057-6062, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704832

RESUMO

BACKGROUND/AIM: The prognosis of patients with osteosarcoma is poor; therefore, new treatment strategies are urgently needed. Phosphodiesterase 2 (PDE2) is one of the 11 families (PDE1-PDE11) of the phosphodiesterase superfamily that regulates the intracellular concentrations and effects of cAMP and cGMP. This in vitro study was performed to investigate the role of PDE2 in human oral osteosarcoma HOSM-1 cells. MATERIALS AND METHODS: PDE2 expression was measured by a cAMP-PDE assay and real-time-PCR. The effects of the PDE2-specific inhibitors, erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), 8-bromo-cAMP, and 8-bromo-cGMP on cell proliferation and migration were assessed. RESULTS: PDE2 activity and PDE2A mRNA expression were detected in HOSM-1 cells. Cell proliferation was inhibited by EHNA and 8-bromo-cAMP but not by 8-bromo-cGMP. Cell migration was stimulated by EHNA and 8-bromo-cGMP, but it was inhibited by 8-bromo-cAMP. CONCLUSION: Cell proliferation is regulated by PDE2-cAMP signaling and cell migration is regulated by PDE2-cGMP signaling in HOSM-1 cells.


Assuntos
Neoplasias Ósseas/patologia , Movimento Celular , Proliferação de Células , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Neoplasias Bucais/patologia , Osteossarcoma/patologia , Adenina/análogos & derivados , Adenina/farmacologia , Apoptose , Compostos de Benzil/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/enzimologia , Ciclo Celular , AMP Cíclico/farmacologia , GMP Cíclico/análogos & derivados , GMP Cíclico/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/genética , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/enzimologia , Osteossarcoma/tratamento farmacológico , Osteossarcoma/enzimologia , Transdução de Sinais , Células Tumorais Cultivadas
5.
Anticancer Res ; 38(12): 6715-6720, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30504381

RESUMO

BACKGROUND/AIM: Due to its abilities of substance adsorption and intracellular transportation, hydroxyapatite is a potential carrier in drug delivery systems (DDS). This in vitro study investigated whether newly-developed, highly-dispersive calcined hydroxyapatite nanoparticles with an average grain diameter of 20 nm (nano-SHAP) were suitable as a DDS for the drugs zoledronic acid (ZA), cisplatin, and carboplatin. MATERIAL AND METHODS: The effects of drug-bearing nano-SHAP on cell proliferation were assessed using three human oral squamous cell carcinoma cell lines (HSC-4, KOSC, and SAS) and one human breast cancer cell line (MCF-7). RESULTS: Nano-SHAP alone did not affect proliferation of any cell line until a concentration of 1 µg/ml was reached. Although the effective concentration of ZA in ZA-bearing nano-SHAP differed, it inhibited cell proliferation better than ZA alone. Cisplatin and carboplatin-bearing nano-SHAP had the same effect as these drugs alone. CONCLUSION: The nano-SHAP system is of potential use as a drug delivery system.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células Escamosas/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Durapatita/química , Neoplasias Bucais/tratamento farmacológico , Nanopartículas/química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/administração & dosagem , Cisplatino/farmacologia , Relação Dose-Resposta a Droga , Portadores de Fármacos , Humanos , Células MCF-7 , Neoplasias Bucais/patologia , Ácido Zoledrônico/administração & dosagem , Ácido Zoledrônico/farmacologia
6.
Cancer Med ; 5(6): 1004-12, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26880699

RESUMO

Cetuximab is remarkable for the relatively high rate and severity of hypersensitivity reactions (HR) being reported in the literature. Screening for cetuximab-specific IgE in serum via immunoassay has been found to be useful in preventing HR; however, these tests are known to have a low positive predictive rate. In an attempt to remedy this, we evaluated the interaction between cetuximab and IgE on basophils for predicting severe cetuximab-induced HR. Twelve head and neck cancer patients were enrolled in this single-institution study: four with a history of cetuximab-induced HR and eight with no such history. Cetuximab-specific and galactose-α-1,3-galactose (α-gal) specific IgEs in serum were measured in vitro using an enzyme-linked immunosorbent assay (ELISA). IgE-cetuximab binding on basophils was also analyzed to evaluate the decrease in cetuximab molecules on basophils after dissociation of IgE from FcεRI. The positive predictive value associated with the presence of cetuximab- or α-gal-specific IgE in serum was found to be only 0.67, whereas the negative predictive value was 1.00. On the other hand, in all four patients who developed HR, the cetuximab molecules on basophils were decreased significantly due to the dissociation of IgE from basophils (P < 0.05). However, this was not the case in patients who did not develop HR. In conclusion, our results strongly imply that the IgE-cetuximab interaction on basophils may be key to developing improved methods for predicting severe cetuximab-induced HR.


Assuntos
Antineoplásicos/efeitos adversos , Basófilos/imunologia , Cetuximab/efeitos adversos , Hipersensibilidade a Drogas/diagnóstico , Hipersensibilidade a Drogas/imunologia , Imunoglobulina E/imunologia , Idoso , Idoso de 80 Anos ou mais , Especificidade de Anticorpos/imunologia , Antineoplásicos/uso terapêutico , Basófilos/metabolismo , Cetuximab/uso terapêutico , Hipersensibilidade a Drogas/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Neoplasias de Cabeça e Pescoço/complicações , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Imunoglobulina E/sangue , Masculino , Pessoa de Meia-Idade , Diester Fosfórico Hidrolases/metabolismo , Prognóstico , Pirofosfatases/metabolismo
7.
Cell Signal ; 26(9): 1807-17, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24705027

RESUMO

Cyclic nucleotide phosphodiesterases (PDEs) regulate the intracellular concentrations and effects of adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP). The role of PDEs in malignant tumor cells is still uncertain. The role of PDEs, especially PDE2, in human malignant melanoma PMP cell line was examined in this study. In PMP cells, 8-bromo-cAMP, a cAMP analog, inhibited cell growth and invasion. However, 8-bromo-cGMP, a cGMP analog, had little or no effect. PDE2 and PDE4, but not PDE3, were expressed in PMP cells. Growth and invasion of PMP cells were inhibited by erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), a specific PDE2 inhibitor, but not by rolipram, a specific PDE4 inhibitor. Moreover, cell growth and invasion were inhibited by transfection of small interfering RNAs (siRNAs) specific for PDE2A and a catalytically-dead mutant of PDE2A. After treating cells with EHNA or rolipram, intracellular cAMP concentrations were increased. Growth and invasion were stimulated by PKA14-22, a PKA inhibitor, and inhibited by N(6)-benzoyl-c AMP, a PKA specific cAMP analog, whereas 8-(4-chlorophenylthio)-2'-O-methyl-cAMP, an Epac specific cAMP analog, did not. Invasion, but not growth, was stimulated by A-kinase anchor protein (AKAP) St-Ht31 inhibitory peptide. Based on these results, PDE2 appears to play an important role in growth and invasion of the human malignant melanoma PMP cell line. Selectively suppressing PDE2 might possibly inhibit growth and invasion of other malignant tumor cell lines.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Melanoma/enzimologia , 8-Bromo Monofosfato de Adenosina Cíclica/farmacologia , Adenina/análogos & derivados , Adenina/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , GMP Cíclico/análogos & derivados , GMP Cíclico/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/genética , Humanos , Melanoma/metabolismo , Melanoma/patologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Rolipram/farmacologia
8.
Case Rep Dent ; 2013: 145282, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23533821

RESUMO

Ameloblastomas frequently occur in relatively young people, but are rarely seen in people aged 80 years or older. We report a case of mandibular ameloblastoma in an elderly patient with a review of the literature. The patient was a 82-year-old man who noticed swelling of the gingiva approximately 2 weeks prior to his initial visit. Computed tomography showed a radiolucent area with little radiopacity. Internal uniformity was observed at the site, with thinning of cortical bone which lacked continuity in some areas. The excision and curettage were performed under general anaesthesia. No recurrence has been observed 14 months after surgery.

9.
Oncol Rep ; 29(4): 1275-84, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23381931

RESUMO

The prognosis for malignant melanoma is poor; therefore, new diagnostic methods and treatment strategies are urgently needed. Phosphodiesterase 2 (PDE2) is one of 21 phosphodiesterases, which are divided into 11 families (PDE1-PDE11). PDE2 hydrolyzes cyclic AMP (cAMP) and cyclic GMP (cGMP), and its binding to cGMP enhances the hydrolysis of cAMP. We previously reported the expression of PDE1, PDE3 and PDE5 in human malignant melanoma cells. However, the expression of PDE2 in these cells has not been investigated. Herein, we examined the expression of PDE2A and its role in human oral malignant melanoma PMP cells. Sequencing of RT-PCR products revealed that PDE2A2 was the only variant expressed in PMP cells. Four point mutations were detected; one missense mutation at nucleotide position 734 (from C to T) resulted in the substitution of threonine with isoleucine at amino acid position 214. The other three were silent mutations. An in vitro migration assay and a terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay revealed that suppressing PDE2 activity with its specific inhibitor, erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA), had no impact on cell motility or apoptosis. Furthermore, the cytotoxicity of EHNA, assessed using a trypan blue exclusion assay, was negligible. On the other hand, assessment of cell proliferation by BrdU incorporation and cell cycle analysis by flow cytometry revealed that EHNA treatment inhibited DNA synthesis and increased the percentage of G2/M-arrested cells. Furthermore, cyclin A mRNA expression was downregulated, while cyclin E mRNA expression was upregulated in EHNA-treated cells. Our results demonstrated that the PDE2A2 variant carrying point mutations is expressed in PMP cells and may affect cell cycle progression by modulating cyclin A expression. Thus, PDE2A2 is a possible new molecular target for the treatment of malignant melanoma.


Assuntos
Adenina/análogos & derivados , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , DNA/biossíntese , Melanoma/metabolismo , Neoplasias Bucais/metabolismo , Adenina/farmacologia , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/genética , Ciclina A/genética , Ciclina A/metabolismo , DNA/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologia , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/patologia , Mutação
10.
Exp Ther Med ; 4(2): 205-210, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22970026

RESUMO

Phosphodiesterases (PDEs) are important regulators of signal transduction processes. Eleven PDE gene families (PDE1-11) have been identified and several PDE isoforms are selectively expressed in various cell types. PDE4 family members specifically hydrolyze cyclic AMP (cAMP). Four genes (PDE4A-D) are known to encode PDE4 enzymes, with additional diversity generated by the use of alternative mRNA splicing and the use of different promoters. While PDE4 selective inhibitors show therapeutic potential for treating major diseases such as asthma and chronic obstructive pulmonary disease, little is known concerning the role of PDE4 in malignant melanoma. In this study, we examined the role of PDE4 in mouse B16-F10 melanoma cells. In these cells, PDE4 activity was found to be ∼60% of total PDE activity. RT-PCR detected only PDE4B and PDE4D mRNA. Cell growth was inhibited by the cAMP analog, 8-bromo-cAMP, but not by the specific PDE4 inhibitors, rolipram and denbufylline, which increased intracellular cAMP concentrations. Finally, migration of the B16-F10 cells was inhibited by the PDE4 inhibitors and 8-bromo-cAMP, while migration was increased by a protein kinase A (PKA) inhibitor, PKI(14-22), and was not affected by 8-pCPT-2'-O-Me-cAMP, which is an analog of exchange protein activated by cAMP (Epac). The inhibitory effect of rolipram on migration was reversed by PKI(14-22). Based on these results, PDE4 appears to play an important role in the migration of B16-F10 cells, and therefore may be a novel target for the treatment of malignant melanoma.

11.
Anticancer Res ; 30(2): 355-8, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20332439

RESUMO

BACKGROUND: Eleven phosphodiesterase (PDE) gene families (PDE1-11) have been identified, and some PDE isoforms are selectively expressed in various cell types. Previously, we reported PDE1, PDE3 and PDE4 expressions in human malignant melanoma cells. However, the expression and role of PDE5 in malignant melanoma cells is not clear. Therefore, we characterized PDE5 in human malignant melanoma MAA cells. MATERIALS AND METHODS: PDE5 activity and PDE5A mRNA expression were investigated in MAA cells. The full open reading frames for human PDE5A1 were sequenced. Effects of PDE5 inhibitors on cell growth were determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assays. RESULTS: PDE5 activity and PDE5A1 mRNA expression were detected in MAA cells. The nucleotide sequence of PDE5A1 was identical to that of human PDE5A1, previously published. Two PDE5 inhibitors inhibited the growth of cells. CONCLUSION: PDE5A1 mRNA is expressed and may play an important role in the growth of human malignant melanoma MAA cells.


Assuntos
Proliferação de Células , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Melanoma/metabolismo , Melanoma/patologia , Western Blotting , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/genética , Humanos , Melanoma/genética , Inibidores da Fosfodiesterase 5 , Inibidores de Fosfodiesterase/farmacologia , Purinonas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
13.
Cardiovasc Hematol Agents Med Chem ; 7(3): 206-11, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19689259

RESUMO

Cyclic adenosine 3'5'-monophosphate (cAMP) and cyclic guanosine 3'5'-monophosphate (cGMP) are critical intracellular messengers involved in transduction of signals generated by a wide variety of extracellular stimuli, including growth factors, cytokines, peptide hormones, light and neurotransmitters. These messengers modulate many fundamental biological processes, including myocardial contractility, platelet aggregation, vascular smooth muscle relaxation, proliferation and apoptosis, etc. Cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and cGMP, and are important in regulating intracellular concentrations and biological actions of these signal-transducing molecules. These enzymes contain at least 11 highly regulated and structurally related gene families (PDE1-11). In this review, we will discuss some general information of PDEs and then focus on PDE3 gene family, including the molecular biology, structure, function and potential as therapeutic targets. Furthermore, we show the possibilities of PDE3 as therapeutic targets in malignant tumor cells and salivary gland.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/análise , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Expressão Gênica , Coração , Humanos , Miocárdio/enzimologia , Neoplasias/enzimologia , Oócitos/enzimologia , Glândulas Salivares/enzimologia
14.
Anticancer Res ; 29(4): 1119-22, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19414353

RESUMO

BACKGROUND: Differentiation-inducing factor 1 [DIF-1; 1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl) hexan-1-one] from Dictyostelium discoideum exhibits antiproliferative activity in mammalian cells. We have previously shown that phosphodiesterase 1 (PDE1) is a pharmacological target of DIF-1, but there are no reports of PDE1 in human malignant melanoma cells. Therefore, we characterized PDE1 in human malignant melanoma MAA cells. MATERIALS AND METHODS: PDE1 mRNA expression was investigated in MAA cells. The full open reading frames for human PDE1C1 and PDE1C3 were cloned. Cell growth was determined by MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] assay. RESULTS: PDE1C mRNA expression was detected in MAA cells. The nucleotide sequence of PDE1C1 was identical to that of human PDE1C1, previously published. At nucleotide 2246 in PDE1C3, A was replaced by G, but this did not change the encoded amino acid. Cell growth was inhibited by the PDE1 inhibitor vinpocetin. CONCLUSION: PDE1C mRNA is expressed and may play an important role in human malignant melanoma MAA cells.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/metabolismo , Melanoma/enzimologia , Anti-Hipertensivos/farmacologia , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , AMP Cíclico/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/antagonistas & inibidores , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/genética , Humanos , Melanoma/genética , Melanoma/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Alcaloides de Vinca/farmacologia
15.
Oncol Rep ; 17(5): 1133-9, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17390056

RESUMO

The activity, expression and function of phosphodiesterase 4 (PDE 4) were investigated in the HMG human gingiva-derived malignant melanoma cell line. A specific PDE4 inhibitor, rolipram, inhibited PDE activity in homogenates of HMG cells, and PDE4B and 4D mRNAs were detected by RT-PCR in RNA from HMG cells. Two specific PDE4 inhibitors, rolipram and Ro-20-1724, and an adenylate cyclase activator, forskolin, increased intracellular cAMP in HMG cells. Cell growth induced by rolipram, Ro-20-1724, and forskolin was inhibited by the H-89 protein kinase A (PKA) inhibitor. However, in contrast to effects of H-89, two other PKA inhibitors, KT5720 and PKI, did not inhibit rolipram-induced cell growth. A cAMP analogue that selectively activates Epac, 8-pCPT-2'-O-Me-cAMP, also promoted the growth of HMG cells. These findings suggested that PDE4, PDE4B and/or 4D regulate cell growth through cAMP targets in the HMG malignant melanoma cell line. There have been no previous studies of positive regulation of cell growth by PDE4 inhibition, suggesting that it may be possible to target PDE4 in therapy for human malignant melanoma.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/biossíntese , Melanoma/enzimologia , Melanoma/patologia , 3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , 3',5'-AMP Cíclico Fosfodiesterases/genética , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Processamento Alternativo , Processos de Crescimento Celular/efeitos dos fármacos , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , AMP Cíclico/análogos & derivados , AMP Cíclico/metabolismo , AMP Cíclico/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Gengiva/patologia , Humanos , Melanoma/genética , Melanoma/metabolismo , Inibidores de Proteínas Quinases/farmacologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética
16.
Arch Oral Biol ; 51(2): 83-8, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16102722

RESUMO

Phosphodiesterase (PDE) 3 has been characterized in isolated rat submandibular acini. PDE3 activity was detected in homogenates of isolated rat submandibular acini; little or no PDE3 activity was found in ducts. About 62% of PDE3 activity in the acini was recovered in the supernatant fractions; 38% in particulate fractions. In the acini, but not ducts, PDE3A mRNA was detected by reverse transcriptase-polymerase chain reaction (RT-PCR). The PDE3-specific inhibitor, cilostamide, increased the ratio of apomucin mRNA/18s rRNA, as quantified by real-time RT-PCR. Our results indicate that PDE3A may be important in regulating cAMP pools that control acini functions.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Glândula Submandibular/enzimologia , 3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , 3',5'-AMP Cíclico Fosfodiesterases/genética , Animais , Células Cultivadas , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3 , Expressão Gênica , Masculino , Inibidores de Fosfodiesterase/farmacologia , Quinolonas/farmacologia , RNA Mensageiro/genética , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Glândula Submandibular/citologia
17.
Cancer Res ; 64(7): 2568-71, 2004 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-15059913

RESUMO

The differentiation-inducing factor-1 (DIF-1) isolated from Dictyostelium discoideum is a potent antiproliferative agent that induces growth arrest and differentiation in mammalian cells in vitro. However, the specific target molecule(s) of DIF-1 has not been identified. In this study, we have tried to identify the target molecule(s) of DIF-1 in mammalian cells, examining the effects of DIF-1 and its analogs on the activity of some candidate enzymes. DIF-1 at 10-40 micro M dose-dependently suppressed cell growth and increased the intracellular cyclic AMP concentration in K562 leukemia cells. It was then found that DIF-1 at 0.5-20 micro M inhibited the calmodulin (CaM)-dependent cyclic nucleotide phosphodiesterase (PDE1) in vitro in a dose-dependent manner. Kinetic analysis revealed that DIF-1 acted as a competitive inhibitor of PDE1 versus the substrate cyclic AMP. Because DIF-1 did not significantly affect the activity of other PDEs or CaM-dependent enzymes and, in addition, an isomer of DIF-1 was a less potent inhibitor, we have concluded that PDE1 is a pharmacological and specific target of DIF-1.


Assuntos
Hexanonas/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Ligação Competitiva , AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1 , Hexanonas/metabolismo , Humanos , Células K562 , Inibidores de Fosfodiesterase/metabolismo
18.
Anticancer Drugs ; 14(5): 377-81, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12782945

RESUMO

Reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed that HOSM-1 cells, an osteosarcoma cell line established from human mandible, expressed mRNA for osteoblastic markers, such as alkaline phosphatase, osteonectin, osteocalcin and parathyroid hormone receptor, thus exhibiting an osteoblastic phenotype. We have investigated a possible role of cyclic nucleotide phosphodiesterases (PDEs) in osteosarcoma cells. RT-PCR analysis revealed that HOSM-1 cells expressed mRNA for PDE4A, 4B and 4C. In addition, rolipram, a specific inhibitor of PDE4, inhibited HOSM-1 cell proliferation. The finding that PDE4 is involved in proliferation of osteosarcoma cells suggests the possibility that PDE4 may be a new target for antitumor therapy.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Antineoplásicos , Neoplasias Ósseas/enzimologia , Osteossarcoma/enzimologia , Inibidores de Fosfodiesterase/farmacologia , 3',5'-AMP Cíclico Fosfodiesterases/genética , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Osteossarcoma/genética , Osteossarcoma/patologia , RNA Neoplásico/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rolipram/farmacologia
19.
Arch Oral Biol ; 48(1): 63-7, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12615143

RESUMO

We have evaluated effects of a phosphodiesterase (PDE) 4 inhibitor on retinoic acid-increased alkaline phosphatase activity in the mouse fibroblastic C3H10T1/2 clone 8 (10T1/2) cell line. 10T1/2 cells were cultured in minimum essential medium (MEM) and 10% fetal bovine serum with or without 1 microM retinoic acid and/or the PDE 4 inhibitor, rolipram, and harvested at specific intervals before measurement of alkaline phosphatase activity, cAMP production in response to parathyroid hormone, osteocalcin synthesis and expression, and phosphodiesterase activity. Retinoic acid-increased alkaline phosphatase activity, and slightly enhanced cAMP production in response to parathyroid hormone. However, it did not affect osteocalcin synthesis and expression. In the presence of retinoic acid, PDE 4 activity was not changed. A PDE 4 inhibitor, rolipram, and cAMP analog, 8-bromo-cAMP dramatically increased retinoic acid's ability to induce alkaline phosphatase activity. This is the first report that PDE 4 may be involved in regulation of retinoic acid-increased alkaline phosphatase activity.


Assuntos
Fosfatase Alcalina/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Rolipram/farmacologia , Tretinoína/farmacologia , 3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , 3',5'-AMP Cíclico Fosfodiesterases/fisiologia , Fosfatase Alcalina/metabolismo , Animais , Linhagem Celular , AMP Cíclico/biossíntese , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Sinergismo Farmacológico , Fibroblastos/enzimologia , Camundongos , Osteocalcina/biossíntese , Osteocalcina/genética , Hormônio Paratireóideo/farmacologia
20.
Anticancer Drugs ; 13(8): 875-80, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12394274

RESUMO

Phosphodiesterase (PDE) 3s have been characterized in human squamous cell carcinoma KB cells. PDE3 activity was detected in homogenates of KB cells. PDE3A and 3B mRNAs were detected by RT-PCR in RNA from KB cells; the nucleotide sequences of the fragments were identical to those of human PDE3A and 3B. Immunoblotting with anti-PDE3 antibodies detected both PDE3A- and 3B-immunoreactive proteins in KB cells. The PDE3-specific inhibitor, cilostamide, inhibited the proliferation of KB cells. Our results indicate that PDE3s may be important regulators of the growth of KB cells. Therefore, PDE3 inhibitors may be potential new drugs for antiproliferative therapies in squamous cell carcinoma in the head and neck.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/fisiologia , Células KB/enzimologia , 3',5'-AMP Cíclico Fosfodiesterases/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3 , Humanos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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