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.
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.
Chelli
Beatrice
B
Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Rossi
Leonardo
L
Da Pozzo
Eleonora
E
Costa
Barbara
B
Spinetti
Francesca
F
Rechichi
Mariarosa
M
Salvetti
Alessandra
A
Lena
Annalisa
A
Simorini
Francesca
F
Vanacore
Renato
R
Scatena
Fabrizio
F
Da Settimo
Federico
F
Gremigni
Vittorio
V
Martini
Claudia
C
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
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