Targeting histone deacetylase 6 mediates a dual anti-melanoma effect: Enhanced antitumor immunity and impaired cell proliferation.

The median survival for metastatic melanoma is in the realm of 8-16 months and there are few therapies that offer significant improvement in overall survival. One of the recent advances in cancer treatment focuses on epigenetic modifiers to alter the survivability and immunogenicity of cancer cells. Our group and others have previously demonstrated that pan-HDAC inhibitors induce apoptosis, cell cycle arrest and changes in the immunogenicity of melanoma cells. Here we interrogated specific HDACs which may be responsible for this effect. We found that both genetic abrogation and pharmacologic inhibition of HDAC6 decreases in vitro proliferation and induces G1 arrest of melanoma cell lines without inducing apoptosis. Moreover, targeting this molecule led to an important upregulation in the expression of tumor associated antigens and MHC class I, suggesting a potential improvement in the immunogenicity of these cells. Of note, this anti-melanoma activity was operative regardless of mutational status of the cells. These effects translated into a pronounced delay of in vivo melanoma tumor growth which was, at least in part, dependent on intact immunity as evidenced by the restoration of tumor growth after CD4+ and CD8+ depletion. Given our findings, we provide the initial rationale for the further development of selective HDAC6 inhibitors as potential therapeutic anti-melanoma agents.

Experiencia clínica prospectiva con glimepirida en pacientes con Diábetes Mellitus tipo 2 en Venezuela / Prospective clinical experience with Glimipiride tolerance in patient with diagnosis of diabetes mellitus type 2 in Venezuela

El objetivo del trabajo fue evaluar la eficacia y tolerancia de glimepirida en pacientes con diagnóstico de Diábetes Mellitus tipo 2 en Venezuela. Mediante un estudio multicéntrico abierto, no randomizado, prospectivo, de Glimepirida en pacientes diabéticos tipo 2. Dosis de inicio: 1 mg de glimepirida, de acuerdo a las respuesta se aumenta la dosis en 1 mg cada 2 semanas hasta alcanzar una glicemia en ayunas menor o igual a 140 mg/dl. El período total de observación fue de 12 semanas. Se realizó un control cada dos semanas. Se estudió una muestra de 258 pacientes diabéticos tipo 2 que no estaban controlados adecuadamente con dieta, ejercicios y/o tratamiento hipoglicemiante, quienes recibieron glimepirida por primera vez o cambiaron su tratamiento a glimepirida. Todos los datos se analizaron mediante la prueba T de Student con dos colas. Se consideró resultado estadísticamente significativo a los valores de p<0.05 en lo que se refiere a disminución de glicemia por cada consulta. Al inicio del estudio la glicemia en ayunas se encontraba en valores de 225,55 ñ 67 mg/dl. Al término del estudio la glicemia obtenida fue 127,80 ñ 42 mg/dl. La glicemia disminuyo en promedio un 44 por ciento luego de 12 semanas de tratamiento. 93 por ciento de casos lograron control adecuado de la glicemia. No se presentaron efectos secundarios en 91 por ciento de los casos. Ocurrieron reacciones adversas en 21 pacientes (9 por ciento de los casos), de los cuales 11 casos corresponden a episodios de hipoglicemia. La hipoglicemia fue leve o moderada en todos los casos no ameritando hospitalización. Glimepirida demostró eficacia terapéutica al disminuir los niveles de glicemia en ayunas a valores menores o iguales a 140 mg/dl en el 79,53 por ciento de los pacientes, significativo estadísticamente, con un excelente perfíl de seguridad (91 por ciento de los casos no reportaron efectos secundarios

Adrenal synthesis of corticosterone in response to ACTH in rats is influenced by leukotriene A4 and by lipoxygenase intermediates.

The possible involvement of the lipoxygenase pathway of arachidonic acid metabolism in the events which take place during ACTH-induced stimulation of corticosterone secretion has been studied using an isolated rat adrenal cell system. Incubation with arachidonic acid resulted in an inhibition of ACTH-stimulated corticosterone production. The lipoxygenase pathway inhibitors nordihydroguaretic acid (NDGA), eicosatetraynoic acid (ETYA) and compound BW755C also produced inhibition of ACTH-stimulated corticosterone synthesis. The concentrations of the inhibitors at which 50% inhibition occurred were 15, 34 and 37 mumol/l respectively. The inhibitions produced by NDGA and ETYA were independent of cyclic AMP output. NDGA also inhibited corticosterone production induced by dibutyryl cyclic AMP but had no effect on corticosterone synthesis induced by pregnenolone. Preincubation of adrenal cells with the lipoxygenase products 5, 12 and 15 hydroxyeicosatetraenoic acid (HETE) and with leukotrienes A4, B4, C4, D4 and E4 resulted in significant inhibitions of corticosterone production in response to ACTH with leukotriene A4 (LTA4) and with 15HETE and 5HETE. Conversely, incubation with glutathione (GSH), which is known to reduce intracellular LTA4 levels, produced stimulation (at 5 mmol GSH/l) and inhibition (at 50 mmol GSH/l) of corticosterone output. These studies suggest that the lipoxygenase pathway may be involved in ACTH-stimulated corticosterone synthesis.

The hypothalamic-pituitary-adrenal axis.

Anterior pituitary corticotrophin cells secrete ACTH as part of a larger precursor molecule, pro-opiomelanocortin. Post-translational cleavage of this precursor yields three major peptides: ACTH, beta-LPH and N-POMC. Experiments both in vivo and in vitro suggest that N-POMC may act as a prohormone amplifier for ACTH-induced adrenal steroidogenesis and as regulator of adrenocortical cell growth. The secretion of POMC is under the control of CRF. These findings are discussed in relation to the pathophysiology of corticotrophinoma. The primary defect in this condition appears to reside at the level of the anterior pituitary cell and is readily amenable to treatment by trans-sphenoidal microsurgery. The estimation of plasma ACTH concentrations is proving useful in the monitoring of various clinical conditions including Addison's disease and congenital adrenal hyperplasia.