Development of resistance to antiglioma agents in rat C6 cells caused collateral sensitivity to doxorubicin
2015
Autori:
Stojković Burić, SonjaPodolski-Renić, Ana
Dinić, Jelena
Stankovic, Tijana
Banković, Jasna Z.
Hadzic, Stefan
Paunovic, Verica
Isakovic, Aleksandra
Tanić, Nikola
Pešić, Milica
Tip dokumenta:
Članak u časopisu (Objavljena verzija)
Metapodaci
Prikaz svih podataka o dokumentuApstrakt:
Chemoresistance is a severe limitation to glioblastoma (GBM) therapy and
there is a strong need to understand the underlying mechanisms that
determine its response to different chemotherapeutics. Therefore, we
induced resistance in C6 rat glioma cell line, which considerably
resembles the characteristics of human GBM. The resistant phenotype was
developed by 3-bis (2-chloroethyl)-1-nitrosourea (BCNU), one of the most
commonly used therapeutic drug in the course of GBM treatment. After
confirmation of the cross-resistance to cisplatin (CPt) and temozolomide
(TMZ) in newly established RC6 cell line, we examined cell death
induction and DNA damage by these drugs. Resistance to apoptosis and
deficiency in forming DNA double-strand breaks was followed by
significant decrease in the mRNA expression of pro-apoptotic and
anti-apoptotic genes. The development of drug resistance was associated
with significant increase in reactive oxygen species (ROS) and decrease
in oxidized to reduced gluthatione ratio in RC6 cell line indicating a
reduced level of oxidative stress. The mRNA expression levels of
manganese superoxid dismutase (MnSOD), inducible nitric oxide synthase
(iNOS) and gluthatione peroxidase (GPx) were increased while
hypoxia-inducible factor 1-alpha (HIF-1 alpha) was decreased in RC6
compared to C6 cells. This was in line with obtained changes in ROS
content and increased antioxidative capacity of RC6 cells. Importantly,
RC6 cells demonstrated collateral sensitivity to doxorubicin (DOX). The
analysis of this phenomenon revealed increased accumulation of DOX in
RC6 cells due to their adaptation to high ROS content and acidification
of cytoplasm. In conclusion, newly established RC6 rat glioma cell line
could be used as a starting material for the development of allogenic
animal model and preclinical evaluation of new antiglioma agents.
Collateral sensitivity to DOX obtained after BCNU treatment may prompt
new studies aimed to find efficient delivery of DOX to the glioma site
in brain. (C) 2015 Elsevier Inc. All rights reserved.
Napomena:
Ključne reči:
Glioma; Drug resistance; Carmustine; Doxorubicin; Antioxidant capacity; Collateral sensitivityIzvor:
Experimental Cell Research, 2015, 335, 2, 248-257Finansiranje / projekti:
- Identifikacija molekularnih markera za predikciju progresije tumora, odgovora na terapiju i ishoda bolesti (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41031)
- Modulacija signalnih puteva koji kontrolišu intracelularni energetski balans u terapiji tumora i neuro-imuno-endokrinih poremećaja (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41025)
DOI: 10.1016/j.yexcr.2015.05.018
ISSN: 0014-4827
PubMed: 26026740