Suppression of oxidative phosphorylation confers resistance against bevacizumab in experimental glioma

Abstract

Although bevacizumab initially shows high response rates in gliomas and other tumours, therapy resistance usually develops later. Because anti-angiogenic agents are supposed to induce hypoxia, we asked whether rendering glioma cells independent of oxidative phosphorylation modulates their sensitivity against hypoxia and bevacizumab. LNT-229 glioma cells without functional mitochondria (rho ) and control (rho ) cells were generated. LNT-229 rho -cells displayed reduced expression of oxidative phosphorylation-related genes and diminished oxygen consumption. Conversely, glycolysis was up-regulated in these cells, as shown by increased lactate production and stronger expression of glucose transporter-1 and lactate dehydrogenase-A. However, hypoxia-induced cell death in vitro was nearly completely abolished in the LNT-229 rho -cells, these cells were more sensitive towards glucose restriction and the treatment with the glycolysis inhibitor 2-deoxy-D-glucose. In an orthotopic mouse xenograft experiment, bevacizumab induced hypoxia as reflected by elevated Hypoxia-inducible factor 1-alpha staining in both, rho - and rho -tumours. However, it prolonged survival only in the mice bearing rho -tumours (74 days vs. 105 days, p = 0.024 log-rank test) and had no effect on survival in mice carrying LNT-229 rho -tumours (75 days vs. 70 days, p = 0.52 log-rank test). Interestingly, inhibition of glycolysis in vivo with 2-deoxy-D-glucose re-established sensitivity of rho -tumours against bevacizumab (98 days vs. 80 days, p = 0.0001). In summary, ablation of oxidative phosphorylation in glioma cells leads to a more glycolytic and hypoxia-resistant phenotype and is sufficient to induce bevacizumab-refractory tumours. These results add to increasing evidence that a switch towards glycolysis is one mechanism how tumour cells may evade anti-angiogenic treatments and suggest anti-glycolytic strategies as promising approaches to overcome bevacizumab resistance.

Linking epigenetic signature and metabolic phenotype in IDH mutant and IDH wildtype diffuse glioma

“…Strikingly, patients who showed a mitochondrial signature in their tumour tissue had significantly better overall survival following Bev treatment. These findings are consistent with experimental data demonstrating that glioma cells without functional mitochondria are resistant to Bev [51]. Although this finding needs to be validated in larger cohorts of patients, these pilot data are compatible with the hypothesis that tumours with a mitochondrial signature are susceptible to anti‐angiogenic therapy because they are less capable of adapting their metabolism to conditions of Bev‐induced hypoxia.…”

Warburg effect in colorectal cancer: the emerging roles in tumor microenvironment and therapeutic implications

“…Upregulation of HIF-1a can promote neovascularization by promoting tumor cells to produce pro-angiogenic factors such as PDGF-B, FGF-2, VEGF-A, VEGFR1 and angiopoietins [ 252 ]. Hence, highly glycolytic metabolism can be considered as a metabolic feature regarding the resistance to Bevacizumab [ 249 , 253 ]. Furthermore, Xu et al found that CRC cells refractory to bevacizumab treatment not only undergo hyperactive glycolytic phenotype, but also occur persistent impairment of mitochondria [ 254 ].…”

Rescue of 2-Deoxyglucose Side Effects by Ketogenic Diet

“…The development of a more glycolytic phenotype as an escape mechanism has been postulated in bevacizumab treated tumor cells [35]. Our group reported that in an orthotopic mouse xenograft model, glioma with impaired oxidative phosphorylation were resistant to treatment with bevacizumab, and treatment with 2-DG re-established sensitivity to bevacizumab [36]. Therefore, antagonizing glycolysis and neoangiogenesis together could be a promising therapeutic concept.…”