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Chloroquine-induced autophagic vacuole accumulation and cell death in glioma cells is p53 independent.


Posted on: 04/23/2010

Neuro Oncol. 2010 May;12(5):473-81. Epub 2010 Jan 27.

Chloroquine-induced autophagic vacuole accumulation and cell death in glioma cells is p53 independent.

Geng Y, Kohli L, Klocke BJ, Roth KA.

Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0017, USA.

 

Abstract

Glioblastoma (GBM) is a high-grade central nervous system malignancy and despite aggressive treatment strategies, GBM patients have a median survival time of just 1 year. Chloroquine (CQ), an antimalarial lysosomotropic agent, has been identified as a potential adjuvant in the treatment regimen of GBMs. However, the mechanism of CQ-induced tumor cell death is poorly defined. We and others have shown that CQ-mediated cell death may be p53-dependent and at least in part due to the intrinsic apoptotic death pathway. Here, we investigated the effects of CQ on 5 established human GBM lines, differing in their p53 gene status. CQ was found to induce a concentration-dependent death in each of these cell lines. Although CQ treatment increased caspase-3-like enzymatic activity in all 5 cell lines, a broad-spectrum caspase inhibitor did not significantly attenuate death. Moreover, CQ caused an accumulation of autophagic vacuoles in all cell lines and was found to affect the levels and subcellular distribution of cathepsin D, suggesting that altered lysosomal function may also play a role in CQ-induced cell death. Thus, CQ can induce p53-independent death in gliomas that do not require caspase-mediated apoptosis. To potentially identify more potent chemotherapeutics, various CQ derivatives and lysosomotropic compounds were tested on the GBM cells. Quinacrine and mefloquine were found to be more potent than CQ in killing GBM cells in vitro and given their superior blood-brain barrier penetration compared with CQ may prove more efficacious as chemotherapeutic agents for GBM patients.

 

 PMID: 20406898 [PubMed - in process] 

  

 Publication Types: 

Research Support, N.I.H., Extramural

Grant Support:

NS35107/NS/NINDS NIH HHS/United States

NS41962/NS/NINDS NIH HHS/United States

NS47466/NS/NINDS NIH HHS/United States

NS57098/NS/NINDS NIH HHS/United States

P50CA097247/CA/NCI NIH HHS/United States

R01 CA134773/CA/NCI NIH HHS/United States 

 

 


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