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1.
Life Sci ; 182: 57-64, 2017 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-28623006

RESUMEN

AIMS: First proof to show that (-)-deprenyl/selegiline (DEP), the first selective inhibitor of MAO-B, later identified as the first ß-phenylethylamine (PEA)-derived synthetic catecholaminergic activity enhancer (CAE) substance and (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine (BPAP), the tryptamine-derived presently known most potent, selective, synthetic enhancer substance, are specific markers of unknown enhancer-sensitive brain regulations. MAIN METHODS: Longevity study disclosing the operation of tumor-manifestation-suppressing (TMS) regulation in rat brain. Immonohistochemical identification of a fibromyxosarcoma in rats. Experiments with human medulloblastoma cell lines. Analysis of the mechanism of action of enhancer substances. KEY FINDINGS: Whereas 20/40 saline-treated rats manifested a fibromyxosarcoma, in groups of rats treated with 0.001mg/kg DEP: 15/40 rats; with 0.1mg/kg DEP: 11/40 rats (P<0.01); with 0.0001mg/kg BPAP: 8/40 rats (P<0.001); with 0.05mg/kg BPAP: 7/40 rats (P<0.01) manifested the tumor. Experiments with human medulloblastoma cell lines, HTB-186 (Daoy); UW-228-2, showed that BPAP was devoid of direct cytotoxic effect on tumor cells, and did not alter the direct cytotoxic effectiveness of temozolomide, cisplatin, etoposide, or vincristine. Interaction with distinct sites on vesicular monoamine-transporter-2 (VMAT2) is the main mechanism of action of the enhancer substances which clarifies the highly characteristic bi-modal, bell-shaped concentration-effect curves of DEP and BPAP. SIGNIFICANCE: Considering of the safeness of the enhancer substances and the finding that DEP and BPAP, specific markers of unknown enhancer sensitive brain regulations, detected the operation of an enhancer-sensitive TMS-regulation in rat brain, it seems reasonable to test in humans low dose DEP or BPAP treatment against the spreading of a malignant tumor.


Asunto(s)
Benzofuranos/farmacología , Encéfalo/efectos de los fármacos , Longevidad/efectos de los fármacos , Inhibidores de la Monoaminooxidasa/farmacología , Selegilina/farmacología , Animales , Antineoplásicos/farmacología , Benzofuranos/administración & dosificación , Encéfalo/metabolismo , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Fibrosarcoma/prevención & control , Humanos , Masculino , Meduloblastoma/tratamiento farmacológico , Inhibidores de la Monoaminooxidasa/administración & dosificación , Ratas , Ratas Wistar , Selegilina/administración & dosificación
2.
Folia Neuropathol ; 54(2): 105-13, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27543768

RESUMEN

Epigenetic alterations have been implicated in cancer development. DNA methylation modulates gene expression, which is catalyzed by DNA methyltransferases (DNMTs). The objective of our study was to evaluate expression of DNMTs in medulloblastoma and analyze its correlation with clinical features. Nuclear expression of DNMT1, DNMT3A and DNMT3B was analyzed in human primary medulloblastoma of 44 patients using immunohistochemistry. Correlation of expression of DNMT levels with classical histological subtypes, novel molecular subgroups and survival of patients was analyzed. Elevated expression of DNMT1, DNMT3A and DNMT3B was observed in 63.64%, 68.18% and 72.73% of all cases, respectively. None of them showed a correlation with classical histology or survival. Concerning molecular subtypes, significantly higher expression of DNMT1 was observed in the SHH group compared to non-SHH samples (p = 0.02), but without significant difference in DNMT3A or DNMT3B levels between any subtypes. In conclusion, DNMT1, DNMT3A and DNMT3B are highly expressed in human medulloblastoma samples, suggesting that promoter hypermethylation may play a role in medulloblastoma development. Demethylation of tumor suppressor gene promoters may be considered as a possible future target in therapy of medulloblastoma.


Asunto(s)
Neoplasias Cerebelosas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/genética , Meduloblastoma/genética , Adolescente , Adulto , Neoplasias Cerebelosas/enzimología , Neoplasias Cerebelosas/patología , Niño , Preescolar , ADN/genética , ADN (Citosina-5-)-Metiltransferasa 1 , Metilación de ADN/fisiología , ADN Metiltransferasa 3A , Femenino , Humanos , Inmunohistoquímica/métodos , Lactante , Masculino , Meduloblastoma/diagnóstico , Meduloblastoma/enzimología , Meduloblastoma/patología , Adulto Joven , ADN Metiltransferasa 3B
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