RESUMO
PURPOSE: Adrenocortical carcinoma (ACC), a rare malignancy of the adrenocortex, is characterized by a crosstalk between the adipose microenvironment and tumor. Here, we assessed the involvement of carbonic anhydrase (CA) enzymes III and IX (CAIII and CAIX), in the metabolic alterations of the adipose tissue characterizing obesity and in the local crosstalk between the tumor adipose microenvironment and ACC. RESULTS/METHODS: CAIII and CAIX expression is altered in visceral adipose tissue (VAT) in obesity and in ACC. A significant CAIX upregulation was present in ACC at advanced stages (n = 14) (fold increase FI = 7.4 ± 0.1, P < 0.05) associated with lower CAIII levels (FI = 0.25 ± 0.06, P < 0.001), compared with lower stages (n = 9). In vitro coculture between visceral adipose stem cells (ASCs) and ACC cell lines, H295R and MUC-1, mimicking the interaction occurring between VAT and advanced ACC, showed a significant CAIX upregulation in H295R but not in MUC-1 cells, and a decreased expression of CAIII. The effect on adipose cells was different when cocultured with H295R or MUC-1 cells. Coculture did not modulate CAIII expression in ASCs, which, however, was significantly downregulated with H295R (FI = 0.34 ± 0.11, P < 0.05) and upregulated by MUC-1 when cocultured ASCs were induced to differentiate toward adipocytes, with an expression profile similar to what found in VAT of obese subjects. CAIX expression was markedly increased in ASCs cocultured with H295R and to a less extent following adipogenesis induction (FI = 150.9 ± 46.5 and FI = 4.6 ± 1.1, P < 0.01, respectively). CONCLUSION: Our findings highlight a modulation of CAIII and CAIX in the metabolic crosstalk between ACC and its local adipose microenvironment, suggesting that CAs might represent a potential target for novel anticancer therapies.
Assuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Anidrase Carbônica III , Anidrases Carbônicas , Humanos , Anidrase Carbônica IX , Antígenos de Neoplasias/metabolismo , Anidrases Carbônicas/metabolismo , Obesidade , Microambiente TumoralRESUMO
A mild, efficient and one pot procedure to access benzoxazoles using easily accessible acylselenoureas as starting materials has been discovered. Mechanistic studies revealed a pH dependent intramolecular oxidative deselenization, with ring closure due to an intramolecular nucleophilic attack of a phenoxide ion. All the benzoxazoles herein reported possessed a primary sulfonamide zinc binding group and showed effective inhibitory action on the enzymes, carbonic anhydrases.
Assuntos
Amidas/farmacologia , Benzoxazóis/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Compostos Organosselênicos/química , Ureia/análogos & derivados , Amidas/síntese química , Amidas/química , Benzoxazóis/síntese química , Benzoxazóis/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Oxirredução , Relação Estrutura-Atividade , Ureia/químicaAssuntos
Antibióticos Antineoplásicos/farmacocinética , Leucemia/metabolismo , Leucemia/patologia , Microscopia de Fluorescência/métodos , Espectrometria de Fluorescência/métodos , Transporte Biológico , Células HL-60 , Humanos , Microscopia de Fluorescência/instrumentação , Espectrometria de Fluorescência/instrumentaçãoRESUMO
Vinorelbine (VNR) is a new semi-synthetic Vinca rosea alkaloid that has been employed both in combination and as a single agent, showing a significant antitumour activity. Since little is known about VNR in human leukemia, we studied the in vitro cytotoxic effect of VNR on peripheral blood lymphocytes from 18 patients affected by B-chronic lymphocytic leukemia (CLL), employing the INT assay. VNR inhibited fresh B-CLL cells from 15/18 patients in primary cultures, the ID50 doses ranging from 4 ng/ml to 83 micrograms/ml. These data strongly suggest that VNR could be effective in the treatment of B-CLL.
Assuntos
Antineoplásicos Fitogênicos/toxicidade , Linfócitos B/patologia , Leucemia Linfocítica Crônica de Células B/patologia , Vimblastina/análogos & derivados , Idoso , Linfócitos B/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Células Tumorais Cultivadas , Vimblastina/toxicidade , VinorelbinaRESUMO
Hamster embryo brain cells exposed in vitro for 24 hrs. to benzo (a) pyrene and then subcultivated. undergo a morphological transformation. After several passages, transformed cells are capable in most cases of inducing tumors of a special type through intraocular or intracerebral grafting. Histological characterisation of these tumors suggests that they are of glial type. Untreated control brain cells subcultivated for one year, keep their normal characteristics and do not induce tumors when grafted in Hamster.