Metabolic alterations underlying Bevacizumab therapy in glioblastoma cells

Abstract

Anti-VEGF therapy with Bevacizumab is approved for glioblastoma treatment, however, it is known that tumors acquired resistance and eventually became even more aggressive and infiltrative after treatment. In the present study we aimed to unravel the potential cellular mechanisms of resistance to Bevacizumab in glioblastoma in vitro models.Using a panel of glioblastoma cell lines we found that Bevacizumab is able to block the secreted VEGF by the tumor cells and be internalized to the cytoplasm, inducing cytotoxicity in vitro. We further found that Bevacizumab increases the expression of hypoxic (HIF-1α and CAIX) and glycolytic markers (GLUT1 and MCT1), leading to higher glucose uptake and lactate production. Furthermore, we showed that part of the consumed glucose by the tumor cells can be stored as glycogen, hampering cell dead following Bevacizumab treatment. Importantly, we found that this change on the glycolytic metabolism occurs independently of hypoxia and before mitochondrial impairment or autophagy induction. Finally, the combination of Bevacizumab with glucose uptake inhibitors decreased in vivo tumor growth and angiogenesis and shift the expression of glycolytic proteins.In conclusion, we reported that Bevacizumab is able to increase the glucose metabolism on cancer cells by abrogating autocrine VEGF in vitro. Define the effects of anti-angiogenic drugs at the cellular level can allow us to discover ways to revert acquired resistance to this therapeutic approaches in the future.

2-Deoxy-d-Glucose and Its Analogs: From Diagnostic to Therapeutic Agents

“…Bevacizumab -GBM [112] 5 -Fluorouracil -pancreatic cancer [73] Trastuzumab -breast cancer [113] Ferulic acid with irradiation -non-small cell lung carcinoma [114] Radiotherapy -breast cancer [ Despite the numerous preclinical and clinical studies cited above, the use of 2-DG in cancer treatment is still limited. Its rapid metabolism and short half-life (according to Hansen et al, after infusion of 50 mg/kg 2-DG, its plasma half-life was only 48 min [117]) make 2-DG a rather poor drug candidate.…”

TAT-Cx43266-283impairs metabolic plasticity in glioma stem cells in vitro and in vivo

“…Indeed, TAT-Cx43266-283 exerts antitumour effects in different nutrient-depleted media, where it prevents metabolic plasticity and eventually leads to cell death. This is especially relevant considering the growing body of work acknowledging intrinsic and extrinsic metabolic states as key factors in cancer drug resistance 8,10,32,49 .…”

“…In addition to a conferred advantage to survive in nutrient-deprived conditions, metabolic plasticity is responsible for resistance to certain cancer treatments, one of the most relevant hallmarks of GSCs 2,3 . For example, glioma cells adapt to bevacizumab treatment -a common antiangiogenic therapy -by increasing glycolisis 8,32 . Similarly, tumour cells can rewire their metabolism to suit their needs under different environment conditions, which can negatively affect their response to common antitumoral drugs, such as mTOR 9 and glutaminase inhibitors 33 , 5-fluorouracil and metformin, and even to immunotherapy 10 .…”

Paths for Improving Bevacizumab Available in 2018: The ADZT Regimen for Better Glioblastoma Treatment

“…Beyond direct vessel effects, bevacizumab strongly suppressed glioblastoma cell expression of 130 kDa platelet endothelial cell adhesion molecule and slightly reduced proliferation but upregulated matrix metalloproteinase-2 production [20]. Also, for example, bevacizumab is cytotoxic (in vitro at least) to VEGF synthesizing glioblastoma cells by binding to outer cell membrane bound VEGF [21].…”