RESUMEN
Immunosuppression is a life-threatening complication of late cancer stages. In this regard, overproduction in the host plasma of the anti-inflammatory cyclopentenone prostaglandins (CP-PGs), which are strongly antiproliferative at high concentrations, may impair immune function. In fact, lymphoid tissues of tumour-bearing rats accumulated large amounts of CP-PGs while the tumour tissue itself did not. Expression of the CP-PG-induced 72-kDa heat shock protein (hsp70) was elevated in lymphocytes from tumour-bearing animals related to controls. As the capacity for CP-PG uptake by lymphocytes is the same as tumour cells, we investigated whether the latter could overexpress the multidrug resistance-associated protein (MRP1/GS-X pump) which extrudes CP-PGs towards the extracellular space as glutathione S-conjugates. Walker 256 tumour cells extruded 15-fold more S-conjugates than lymphocytes from the same rats (p < 0.001). This did not appear to be related to deficiency in lymphocyte glutathione (GSH) metabolism, since the major GSH metabolic routes are consistent with CP-PG conjugation in lymphocytes. This was not the case, however, for the MRP1/GS-X pump activity in lymphocyte membranes (in pmol/min/mg protein: 3.1 +/- 1.7 from normal rats, 0.2 +/- 0.2 from tumour-bearing animals vs 64.3 +/- 7.0 in tumour cells) which was confirmed by Western blot analysis for MRP1 protein. Transfection of lymphocytes with MRP1 gene completely abolished CP-PG (0-40 microM) toxicity. Taken together, these findings suggest that CP-PG accumulation in lymphocytes may be, at least partially, responsible for cancer immunodeficiency. Clinical approaches for overexpressing MRP1/GS-X pump in lymphocytes could then play a role as a tool for the management of cancer therapeutics.
Asunto(s)
Carcinoma 256 de Walker/metabolismo , Ciclopentanos/metabolismo , Linfocitos/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Neoplasias/patología , Prostaglandinas A/metabolismo , Animales , Supervivencia Celular , Ciclopentanos/química , Citotoxicidad Inmunológica , Glutamato-Cisteína Ligasa/metabolismo , Glutatión/metabolismo , Disulfuro de Glutatión/metabolismo , Glutatión Transferasa/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismo , Síndromes de Inmunodeficiencia/metabolismo , Cinética , Ganglios Linfáticos , Masculino , Familia de Multigenes , Neoplasias/inmunología , Tamaño de los Órganos , Prostaglandinas A/química , Ratas , Ratas Wistar , TimoRESUMEN
The effect of prostaglandins (PGA1 and PGB2) on the replication of Mayaro virus was studied in Vero cells. PGA1 and PGB2 antiviral activity was found to be dose-dependent. However, while 10 µg/ml PGB2 inhibited virus yield by 60 percent, at the same dose PGA1 suppressed virus replication by more than 90 percent. SDS-PAGE analysis of [35S]-methionine-labelled proteins showed that PGA1 did not alter cellular protein synthesis. In infected cells, PGA1 slightly inhibited the synthesis of protein C, while drastically inhibiting the synthesis of glycoproteins E1 and E2
Asunto(s)
Animales , Alphavirus/fisiología , Prostaglandinas A/farmacología , Prostaglandinas B/farmacología , Células Vero/efectos de los fármacos , Replicación Viral/efectos de los fármacos , Infecciones por Alphavirus/tratamiento farmacológico , Alphavirus/efectos de los fármacos , Alphavirus/crecimiento & desarrollo , Glicoproteínas/biosíntesis , Metionina/análisis , Prostaglandinas A/metabolismo , Prostaglandinas A/uso terapéutico , Prostaglandinas B/metabolismo , Prostaglandinas B/uso terapéutico , Proteína C/biosíntesisRESUMEN
The effect of prostaglandins (PGA1 and PGB2) on the replication of Mayaro virus was studied in Vero cells. PGA1 and PGB2 antiviral activity was found to be dose-dependent. However, while 10 micrograms/ml PGB2 inhibited virus yield by 60%, at the same dose PGA1 suppressed virus replication by more than 90%. SDS-PAGE analysis of [35S]-methionine-labelled proteins showed that PGA1 did not alter cellular protein synthesis. In infected cells, PGA1 slightly inhibited the synthesis of protein C, while drastically inhibiting the synthesis of glycoproteins E1 and E2.
Asunto(s)
Alphavirus/fisiología , Prostaglandinas A/farmacología , Prostaglandinas B/farmacología , Células Vero/virología , Replicación Viral/efectos de los fármacos , Alphavirus/efectos de los fármacos , Alphavirus/crecimiento & desarrollo , Infecciones por Alphavirus/tratamiento farmacológico , Animales , Chlorocebus aethiops , Glicoproteínas/biosíntesis , Metionina/análisis , Prostaglandinas A/metabolismo , Prostaglandinas A/uso terapéutico , Prostaglandinas B/metabolismo , Prostaglandinas B/uso terapéutico , Proteína C/biosíntesisRESUMEN
Severe uterine and placental disturbances have been described in diabetes pathology. The relative severity of these changes appears to correlate with high glucose levels in the plasma and incubating environment. In order to characterize changes in eicosanoid production we compared uterine and placental arachidonic acid conversion from control and non-insulin-dependent diabetes mellitus (NIDDM) rats on day 21 of pregnancy, into different prostanoids, namely PGE2, PGF22alpha, TXB2 (indicating the production of TXA2) and 6-keto-PGF1 (indicating the generation of PGI2). PGE2, PGF2alpha and TXB2 production was higher and 6-keto-PGF1alpha was similar in diabetic compared to control uteri. PLA2 activity was found diminished in the NIDDM uteri in comparison to control. A role for PLA2 diminution as a protective mechanism to avoid prostaglandin overproduction in uterine tissue from NIDDM rats is discussed. Placental tissues showed an increment in TXB2 generation and a decrease in 6-keto PGF1alpha level in diabetic rats when compared to control animals. Moreover, when control uterine tissue was incubated in the presence of elevated glucose concentrations (22 mM), similar generation of 6-keto PGF1alpha and elevated production of PGE2, PGF2alpha and TXB2 were found when compared to those incubated with glucose 11 mM. Placental TXB2 production was higher and 6-keto PGF1alpha was lower when control tissues were incubated in the presence of high glucose concentrations. However, high glucose was unable to modify uterine or placental prostanoid production in diabetic rats. We conclude that elevated glucose levels induced an abnormal prostanoid profile in control uteri and placenta, similar to those observed in non-insulin-dependent diabetic tissues.
Asunto(s)
Glucemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Eicosanoides/biosíntesis , Placenta/metabolismo , Embarazo en Diabéticas/metabolismo , Preñez , Útero/metabolismo , 6-Cetoprostaglandina F1 alfa/metabolismo , Animales , Ácidos Araquidónicos/metabolismo , Dinoprost/metabolismo , Dinoprostona/metabolismo , Femenino , Intercambio Materno-Fetal , Embarazo , Prostaglandinas A/metabolismo , Ratas , Ratas Wistar , Tromboxano A2/metabolismo , Tromboxano B2/metabolismoRESUMEN
Las prostaglandinas (PG) E-2 y F-2 alfa tienen variadas acciones fisiologicas y farmacologicas. El presente trabajo es una revision bibliografica de estas acciones, profundizando en los efectos uterinos, farmacocinetica, las indicaciones, precauciones y contraindicaciones en su uso