title: PIGA (N,N-Di-n-butyl-5-chloro-2-(4-chlorophenyl)indol-3-ylglyoxylamide), a new mitochondrial benzodiazepine-receptor ligand, induces apoptosis in C6 glioma cells.
abstract: Mitochondrial benzodiazepine-receptor (mBzR) ligands constitute a heterogeneous class of compounds that show a pleiotropic spectrum of effects within the cells, including the modulation of apoptosis. In this paper, a novel synthetic 2-phenylindol-3-ylglyoxylamide derivative, N,N-di-n-butyl-5-chloro-2-(4-chlorophenyl)indol-3-ylglyoxylamide (PIGA), which shows high affinity and selectivity for the mBzR, is demonstrated to induce apoptosis in rat C6 glioma cells. PIGA was able to dissipate mitochondrial transmembrane potential (DeltaPsim) and to cause a significant cytosolic accumulation of cytochrome c. Moreover, typical features of apoptotic cell death, such as caspase-3 activation and DNA fragmentation, were also detected in PIGA-treated cells. Our data expand the knowledge on mBzR ligand-mediated apoptosis and suggest PIGA as a novel proapoptotic compound with therapeutic potential against glial tumours, in which apoptosis resistance has been reported to be involved in carcinogenesis.
authors.affiliation: Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Chelli
authors.forename: Leonardo
authors.initials: L
authors.lastname: Rossi
authors.forename: Eleonora
authors.initials: E
authors.lastname: Da Pozzo
authors.forename: Barbara
authors.initials: B
authors.lastname: Costa
authors.forename: Francesca
authors.initials: F
authors.lastname: Spinetti
authors.forename: Mariarosa
authors.initials: M
authors.lastname: Rechichi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Salvetti
authors.forename: Annalisa
authors.initials: A
authors.lastname: Lena
authors.forename: Francesca
authors.initials: F
authors.lastname: Simorini
authors.forename: Renato
authors.initials: R
authors.lastname: Vanacore
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Scatena
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
authors.forename: Vittorio
authors.initials: V
authors.lastname: Gremigni
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004249:DNA Damage; D005910:Glioma / Q000473:pathology*; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008024:Ligands; D008564:Membrane Potentials / Q000187:drug effects* / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D008024:Ligands; C503726:N,N-Di-n-butyl-5-chloro-2-(4-chlorophenyl)indol-3-ylglyoxylamide; D011963:Receptors, GABA-A; D045304:Cytochromes c; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases