Inhibition of C6 rat glioma proliferation by [Ru2Cl(Ibp)4] depends on changes in p21, p27, Bax/Bcl2 ratio and mitochondrial membrane potential.
The ruthenium compound [Ru(2)Cl(Ibp)(4)] (or RuIbp) has been reported to cause significantly greater inhibition of C6 glioma cell proliferation than the parent HIbp. The present study determined the effects of 0-72h exposure to RuIbp upon C6 cell cycle distribution, mitochondrial membrane potential, reactive species generation and mRNA and protein expression of E2F1, cyclin D1, c-myc, pRb, p21, p27, p53, Ku70, Ku80, Bax, Bcl2, cyclooxygenase 1 and 2 (COX1 and COX2). The most significant changes in mRNA and protein expression were seen for the cyclin-dependent kinase inhibitors p21 and p27 which were both increased (p<0.05). The marked decrease in mitochondrial membrane potential (p<0.01) and modest increase in apoptosis was accompanied by a decrease in anti-apoptotic Bcl2 expression and an increase in pro-apoptotic Bax expression (p<0.05). Interestingly, COX1 expression was increased in response to a significant loss of prostaglandin E(2) production (p<0.001), most likely due to the intracellular action of Ibp. Future studies will investigate the efficacy of this novel ruthenium-ibuprofen complex in human glioma cell lines in vitro and both rat and human glioma cells growing under orthotopic conditions in vivo.
Benadiba
Marcel
M
Department of Cell and Developmental Biology, University of São Paulo, São Paulo, SP, Brazil.
Dos Santos
Renata Rolim Prudente
RR
Silva
Denise de Oliveira
Dde O
Colquhoun
Alison
A
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D005434:Flow Cytometry; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017975:Ruthenium Compounds / Q000737:chemistry / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017382:Reactive Oxygen Species; D017975:Ruthenium Compounds; D051028:bcl-2-Associated X Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015232:Dinoprostone