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.
Highlights
Gliomas are the most common group of brain tumors, representing approximately 70%
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 found that all cell lines express VEGF in the cytosol and that Beva recognizes an intracellular protein that colocalizes exactly with VEGF, as expected (Figure 1A)
Summary
Gliomas are the most common group of brain tumors, representing approximately 70%. Glioblastoma (GBM) is the most common and aggressive glioma in adults [1,2,3,4]. Standard treatment consists of surgical resection followed by radiotherapy plus concomitant and adjuvant temozolomide chemotherapy. This regimen offers modest benefits with a median overall survival of only 16 months [4,5,6,7,8]. A better understanding of GBM biology and more effective therapeutic options are warranted. New strategies to improve cancer treatment, such as the usage of molecular targeted therapies, that selectively target altered proteins in cancer cells, have been developed [9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
