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The influence of Coenzyme Q on temozolomide therapeutic efficacy in resistant rat C6 glioma

Sonja Stojković1, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Serbia; Ana Podolski-Renić2, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Serbia; Stefan Hadžić3, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Serbia; Jelena Dinić4, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Serbia; Zorica Milošević5, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Serbia; Miodrag Dragoj6, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Serbia; Alicia Martinez González7, Universidad de Castilla-La Mancha, Espana; Víctor Pérez-García8, Universidad de Castilla-La Mancha, Espana; Mario Durán Prado9, Universidad de Castilla-La Mancha, Espana; Milica Pešić10, Institute for Biological Research “Siniša Stanković”, University of Begrade, Serbia


Understanding the mechanisms underlying resistance of glioblastoma could lead to the development of new therapeutic strategies. Therefore, we established and characterized resistant rat C6 glioma cell line. We evaluated its invasiveness in vitro and in orthotopic animal model. The influence of lipophilic antioxidant Coenzyme-Q (CoQ) on temozolomide (TMZ) efficacy was assessed.
C6 cells continuously treated with 3-bis (2-chloroethyl)-1-nitrosourea (BCNU) developed resistance to this drug and to TMZ. The nature of interaction between TMZ and CoQ in sensitive C6 and newly established resistant C6 cell line (RC6) cells was analyzed. For animal studies, adult male Wistar rats, weighing 250–300 g were used. Fluorescently labeled RC6 cells were inoculated in a burr hole 3 mm lateral from the midline and 3 mm anterior of the Bregma. Animals were treated with CoQ for two cycles in a week prior to and a week after TMZ treatment. After 25 days, animals were scarified, the brains were fixed and consecutive coronal sections were cut and stained with propidium iodide.
CoQ enhanced the sensitivity of RC6 cells and synergistically interacted with TMZ. The development of drug resistance was followed by significant increase in ROS production in RC6 cell line, while CoQ was able to decrease it. Addition of CoQ resulted in a substantial decrease in RC6 migration, evaluated by quantification of lamellipodia positive (migrating) cells. Moreover, CoQ decreased invasiveness according to gelatin degradation assay and animal studies.
Development of drug resistance in RC6 cell line resulted in the increased ROS content followed by more aggressive phenotype. CoQ showed a great anti-invasion potential as was observed in our model of resistant RC6 rat glioma.

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