ABSTRACT
The antidiabetic biguanide metformin exerts antiproliferative effects in different solid tumors. However, during preclinical studies, metformin concentrations required to induce cell growth arrest were invariably within the mM range, thus difficult to translate in a clinical setting. Consequently, the search for more potent metformin derivatives is a current goal for new drug development. Although several cell-specific intracellular mechanisms contribute to the anti-tumor activity of metformin, the inhibition of the chloride intracellular channel 1 activity (CLIC1) at G1/S transition is a key events in metformin antiproliferative effect in glioblastoma stem cells (GSCs). Here we tested several known biguanide-related drugs for the ability to affect glioblastoma (but not normal) stem cell viability, and in particular: phenformin, a withdrawn antidiabetic drug; moroxydine, a former antiviral agent; and proguanil, an antimalarial compound, all of them possessing a linear biguanide structure as metformin; moreover, we evaluated cycloguanil, the active form of proguanil, characterized by a cyclized biguanide moiety. All these drugs caused a significant impairment of GSC proliferation, invasiveness, and self-renewal reaching IC50 values significantly lower than metformin, (range 0.054-0.53 mM vs. 9.4 mM of metformin). All biguanides inhibited CLIC1-mediated ion current, showing the same potency observed in the antiproliferative effects, with the exception of proguanil which was ineffective. These effects were specific for GSCs, since no (or little) cytotoxicity was observed in normal umbilical cord mesenchymal stem cells, whose viability was not affected by metformin and moroxydine, while cycloguanil and phenformin induced toxicity only at much higher concentrations than required to reduce GSC proliferation or invasiveness. Conversely, proguanil was highly cytotoxic also for normal mesenchymal stem cells. In conclusion, the inhibition of CLIC1 activity represents a biguanide class-effect to impair GSC viability, invasiveness, and self-renewal, although dissimilarities among different drugs were observed as far as potency, efficacy and selectivity as CLIC1 inhibitors. Being CLIC1 constitutively active in GSCs, this feature is relevant to grant the molecules with high specificity toward GSCs while sparing normal cells. These results could represent the basis for the development of novel biguanide-structured molecules, characterized by high antitumor efficacy and safe toxicological profile.
ABSTRACT
Es conocido el elevado neurotropismo del virus de la inmunodeficiencia humana (VIH), tanto en sus manifestaciones clinico-patologicas como paraclinicas. Dichas manifestaciones pueden ser la consecuencia de la agresion directa del virus sobre el SNC y periferico o proporcionar alteraciones inmunitarias que faciliten la aparicion de infecciones o neoplasias. Existen aspectos controvertidos en esta patologia. Con el proposito de aportar informacion acerca de estos aspectos, mas especificamente sobre la patologia por agresion directa del VIH, se estudiaron 50 pacientes infectados con el virus, 27 en estado II - III del CDC, y 23 en estadio IV, realizando un estudio transversal, clinico paraclinico, (EEG, Potenciales evocados multimodales, Estudio electrico periferico, TAC y estudio del LCR citobioquimico e inmunoproteico), comparando posteriormente los hallazgos obtenidos. El estudio ha evidenciado la afectacion precoz del sistema nervioso en la enfermedad, tanto en el area clinica , neuropsicologica, y estudio del LCR (citobioquimico e inmunoproteico), como en los potenciales evocados auditivos y el estudio electrico periferico. Se constata asimismo un deterioro progresivo en el SNC y periferico en las pruebas relacionadas segun los estudios clinicos existiendo una correlacion casi paralela entre el estudio neuropsicologico, el estudio electrico periferico, la TAC y el EEG
