RESUMEN
Due to wide spreading of inflammatory disease and imperfection of available anti-inflammatory drugs, mainly associated with their serious side effects, searching for new anti-inflammatory agents is a pressing problem. Natural triterpenoids and their synthetic analogs are a promising source of new drugs. In this study, we have investigated the anti-inflammatory and antitumor effects in vivo of the glycyrrhetinic acid derivative soloxolone methyl (SM), or methyl 2-cyano-3,12-dioxo-18ßH-olean-9(ll),l(2)-dien-30-oate. SM was shown to efficiently suppress the development of edema in a mouse model of carrageenan- or histamine-induced acute inflammation. SM also inhibited the tumor growth and reduced the tumor cell count in the ascitic fluid in mice bearing Krebs-2 carcinoma, the development of which is accompanied by an inflammatory process in the surrounding tissues.
Asunto(s)
Carcinoma Krebs 2/tratamiento farmacológico , Ácido Glicirretínico , Animales , Carcinoma Krebs 2/metabolismo , Carcinoma Krebs 2/patología , Ensayos de Selección de Medicamentos Antitumorales , Ácido Glicirretínico/análogos & derivados , Ácido Glicirretínico/química , Ácido Glicirretínico/farmacología , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos ICRRESUMEN
RLS lymphosarcoma characterized by enhanced expression of mdr1a and mdr1b genes encoding P-glycoprotein is insensitive to low doses of cyclophosphamide, but is susceptible to its high doses approximating the maximum tolerated doses. Induction of apoptotic death of RLS cells by high doses of cyclophosphamide was demonstrated by cytofluorometry and electrophoresis. Experiments on RLS(40) tumor cells derived from RLS lymphosarcoma and characterized by more intensive expression of mdr1a/1b genes showed that the therapeutic effects of cyclophosphamide increased under conditions of simultaneous suppression of these genes by specific small interfering RNA (siRNA). These findings suggest that active cyclophosphamide metabolite can be a substrate for P-glycoprotein.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Apoptosis/fisiología , Ciclofosfamida/metabolismo , Regulación Neoplásica de la Expresión Génica/fisiología , Linfoma no Hodgkin/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Ciclofosfamida/farmacología , Electroforesis , Citometría de Flujo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos CBA , ARN Interferente Pequeño/genética , Miembro 4 de la Subfamilia B de Casete de Unión a ATPRESUMEN
The ability of artificial ribonucleases to cause in the concentration-dependent manner death of cancer cells has been studied. The cytotoxic activity of artificial ribonucleases is observed at rather low concentration of these compounds (10(-5) M). Analysis of the mechanism of artificial ribonucleases cytotoxicity revealed that compounds under the study exhibit membranotropic activity in addition to ribonucleases activity found earlier. This activity is responsible for effective penetration of these compounds inside cells. The results obtained show that artificial ribonucleases induce cell death via damage of cells membrane, detachment of plasmalemma and derangement its macromolecular organization. In the case of short-term exposure of cells to the compounds, cells, even with damaged membrane, survive.
Asunto(s)
Antineoplásicos/farmacología , Imidazoles/farmacología , Piperazinas/farmacología , Ribonucleasas/farmacología , Animales , Muerte Celular/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Membrana Celular/efectos de los fármacos , Membrana Celular/ultraestructura , Perros , Humanos , Imidazoles/química , Piperazinas/químicaRESUMEN
Inhibition of p-glycoprotein (PGP) expression and reverse of multidrug resistance (MDR) phenotype in KB-8-5 cells by synthetic 21-bp double-stranded oligoribonucleotides were investigated. siRNA constructs for the efficient down regulation of MDR1 that are active in nanomolar concentrations and cause reversal of MDR phenotype in cells were developed.