Dual-targeting of aberrant glucose metabolism in glioblastoma

Journal of Experimental & Clinical Cancer Research

Kerrie L McDonald³  Philip J Hogg¹  Peter P Luk¹  Sylvia A Chung³  Eric Hau²  Pierre J Dilda¹  Stephanie Decollogne¹  Han Shen³ 

[1] Tumour Metabolism Group, Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, Sydney 2052, NSW, Australia;Cancer Care Centre, St George Hospital, Kogarah 2217, NSW, Australia;Cure Brain Cancer Neuro-Oncology Group, Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, Sydney 2052, Australia

关键词: Apoptosis;    Dichloroacetate;    PENAO;    Metabolism;    Cancer;   

Others  :  1133388
DOI  :  10.1186/s13046-015-0130-0

 received in 2014-12-11, accepted in 2015-01-28,  发布年份 2015

【 摘 要 】

Background

Glioblastoma (GBM) is the most common and malignant primary brain tumor. In contrast to some other tumor types, aberrant glucose metabolism is an important component of GBM growth and chemoresistance. Recent studies of human orthotopic GBM in mice and in situ demonstrated GBM cells rely on both glycolysis and mitochondrial oxidation for glucose catabolism. These observations suggest that the homeostasis of energy metabolism of GBM cells might be further disturbed by dual-inhibition of glucose metabolism. The present study aimed to evaluate the efficacy and the mechanisms of dual-targeting therapy in GBM cells.

Methods

Representative GBM cells (immortalized GBM cell lines and patient-derived GBM cells) and non-cancerous cells were treated with 4-(N-(S-penicillaminylacetyl)amino) phenylarsonous acid (PENAO), an in-house designed novel arsenic-based mitochondrial toxin, in combination with dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor. The efficacy of this combinatorial therapy was evaluated by MTS assay, clonogenic surviving assay and apoptotic assays. The underlying mechanisms of this dual-targeting treatment were unraveled by using mitochondrial membrane potential measurements, cytosol/mitochondrial ROS detection, western blotting, extracellular flux assay and mass spectrometry.

Results

As monotherapies, both PENAO and DCA induced proliferation arrest in a panel of GBM cell lines and primary isolates. PENAO inhibited oxygen consumption, induced oxidative stress and depolarized mitochondrial membrane potential, which in turn activated mitochondria-mediated apoptosis. By combining DCA with PENAO, the two drugs worked synergistically to inhibit cell proliferation (but had no significant effect on non-cancerous cells), impair the clonogenicity, and induce mitochondria-mediated apoptosis. An oxidative stress of mitochondrial origin takes a prominent place in the mechanism by which the combination of PENAO and DCA induces cell death. Additionally, PENAO-induced oxidative damage was enhanced by DCA through glycolytic inhibition which in turn diminished acid production induced by PENAO. Moreover, DCA treatment also led to an alteration in the multidrug resistance (MDR) phenotype of GBM cells, thereby leading to an increased cytosolic accumulation of PENAO.

Conclusions

The findings of this study shed a new light with respect to the dual-targeting of glucose metabolism in GBM cells and the innovative combination of PENAO and DCA shows promise in expanding GBM therapies.

【 授权许可】

   
2015 Shen et al.; licensee BioMed Central.

【 图 表 】

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