Growth inhibitory effects of the Diruthenium-Ibuprofen compound, [Ru2Cl(Ibp) 4], in human glioma cells in vitro and in the rat C6 orthotopic glioma in vivo.
The Diruthenium-Ibuprofen compound [Ru2Cl(Ibp)4] (or RuIbp) is known to cause significant inhibition of C6 rat glioma cell proliferation in vitro. RuIbp increased the expression of cell cycle-related proteins such as p21 and p27 and the pro-apoptotic protein Bax, as well as causing a reduction in mitochondrial membrane potential and a modest increase in apoptosis in vitro. The present study extended these findings by (i) investigating the effects of RuIbp on human glioma cell line proliferation in vitro and (ii) investigating the acute and chronic toxicology of the compound in normal Wistar rats. The compound was then tested for its anti-tumour properties by either chronic 14 days intra-peritoneal (IP) administration or chronic Alzet osmotic pump infusion, in the rat C6 orthotopic glioma model in vivo. The IP injection of RuIbp caused a 41 % inhibition of tumour area without significant toxic effects but with an increase in blood neutrophils and monocytes and a decrease in blood lymphocytes. In an attempt to reduce this effect RuIbp was administered by Alzet osmotic pump infusion directly into the tumour at a dose of 15 mg/kg with an infusion rate of 0.5 µL/h for 14 days. The direct infusion of RuIbp caused a 45 % inhibition of tumour area without alterations in differential blood leukocyte counts. These results prove the efficacy of RuIbp in human glioma cell lines in vitro and in an in vivo glioma model and point to its potential as an inhibitor of tumour growth in vivo.
Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
Marcel
M
Benadiba
Iguatinã
I
de M Costa
Rodrigo L S R
RL
Santos
Fernanda Oliveira
FO
Serachi
Denise
D
de Oliveira Silva
Alison
A
Colquhoun
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D007052:Ibuprofen / Q000737:chemistry*; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012428:Ruthenium / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D012428:Ruthenium; D007052:Ibuprofen