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Development of resistance to antiglioma agents in rat C6 cells caused collateral sensitivity to doxorubicin.

Al's Comment:

 This type of research is brilliant. It is only in a mouse model, so we do not yet know if it applies to humans.  They looked at tumors that became resistant to BCNU and Temodar and found that the changes that allowed the resistance  to these drugs opened the door for different drugs to work.  

Doxorubicin has been shown to be effective against brain tumor cells in the test tube but it is hard to get a high level of it in the brain so it is not used much today. 10 years ago there was a paper (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1635000/) reporting on using Doxorubicin wafers implanted into rat brain tumor and they did pretty well.  It may be time to look at this again especially for recurrent GBMs that became resistant to temodar.


Posted on: 06/03/2015

  Exp Cell Res. 2015 May 27. pii: S0014-4827(15)30001-X. doi: 10.1016/j.yexcr.2015.05.018. [Epub ahead of print]
Development of resistance to antiglioma agents in rat C6 cells caused collateral sensitivity to doxorubicin.
Stojkovi? S1, Podolski-Reni? A1, Dini? J1, Stankovi? T1, Bankovi? J1, Hadži? S1, Paunovi? V2, Isakovi? A2, Tani? N1, Peši? M 3.
 
Author information:
1Institute for Biological Research "Siniša Stankovi?", University of Belgrade, Despota Stefana 142, 11060 Belgrade, Serbia.
2Faculty of Medicine, University of Belgrade, Doktora Suboti?a 8, Belgrade, Serbia.
3Institute for Biological Research "Siniša Stankovi?", University of Belgrade, Despota Stefana 142, 11060 Belgrade, Serbia. Electronic address: camala@ibiss.bg.ac.rs.
 
Abstract
 
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 to 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-α (HIF-1α) 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.
 
Copyright © 2015. Published by Elsevier Inc.

 


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