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

Abstract

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.

Rux largely restores lungs in Iraq PM-exposed mice, Up-regulating regulatory T-cells (Tregs)

“…Ruthenium complexes have been published and identified in recent literature as anti-inflammatory and anti-cancer agents (19–25). RuX as an anti-inflammatory agent may be due to the higher coordination numbers of transition metals (ruthenium and palladium), allowing transition metal complexes to have more diverse molecular geometry, unknown to organic molecules created by carbon (coordination number 4) (26).…”

Spectroscopic studies on interactions of the tetrakis(acetato)chloridodiruthenium(II,III) complex and the Ru2(II,III)-NSAID-derived metallodrugs of ibuprofen and ketoprofen with human serum albumin

“…Previous studies based on circular dichroism (CD) and SDS-PAGE performed in our laboratory suggested that the RuIbp metallodrug binds to HSA and induces conformational changes in the protein secondary structure without causing significant protein cleavage [46]. The present work extends our studies by investigating the interactions of the Ru 2 (II,III) complexes, i.e., RuAc, RuIbp and RuKet, with HSA.…”

“…More interestingly, Ru 2 -NSAID complexes are capable of inhibiting proliferation of glioma cancer cells. RuIbp was shown to exhibit anticancer activity in vitro (in rat and in human glioma cell lines) and also in vivo, thus revealing interesting properties for further studies targeting brain cancer therapy [47]. RuIbp and the analogue complex of Ketoprofen (HKet) ligand, [Ru 2 (Ket) 4 Cl] (or RuKet, figure 1c), display mild anti-proliferative activity in Caco-2 and HT-29 colorectal cancer cells [50].…”

“…A novel class of melallodrugs containing the [Ru 2 (μ-O 2 CR) 4 ] + unit, where the carboxylate anion derives from a pharmaceutical drug, has been prepared, characterized and investigated for biological properties [22,23,[44][45][46][47][48][49]. Notably, the diruthenium complex of the non-steroidal anti-inflammatory drug (NSAID) Ibuprofen (HIbp), [Ru 2 (Ibp) 4 Cl] (or RuIbp, figure 1b), was found to show similar anti-inflammatory properties, but to cause reduced stomach ulceration, when compared to the HIbp parent drug.…”

Unusual Structural Features in the Lysozyme Derivative of the Tetrakis(acetato)chloridodiruthenium(II,III) Complex

“…Compound 1 has been used as a precursor to prepare a novel class of diruthenium(II,III) metallodrugs of the general formula [Ru 2 (RCOO) 4 Cl], where RCOO − is a carboxylate anion derived from a therapeutic drug 10c. In particular, metallodrugs containing carboxylate ligands derived from the nonsteroidal anti‐inflammatory drug ibuprofen10d,e or from γ‐linolenic acid10f,g were found to be active against glioma tumor models and have been investigated for partial elucidation of their mechanism of action. Moreover, the diruthenium–ibuprofenate complex shows anti‐inflammatory properties with reduced gastric ulceration in vivo compared to the ibuprofen parent drug 10h…”