Potential mechanisms of human recombinant arginase I (Co)-PEG5000 [HuArgI (CO) - PRG5000] induced cytotoxicity in glioblastoma cells. (c2018)

Abstract

Glioblastoma multiforme (GBM) is a highly aggressive glioma arising in the central nervous system accounting for more than 70% of all brain tumors. Due to the resistance and complexity of the tumor itself, it is characterized by a low survival rate and decreased prognosis. Therefore, more selective and efficient therapeutic methods for targeting GBM are needed. In this study, we attempted to investigate the potency of arginine depletion to target GBM cells through the use of human recombinant Arginase I cobalt [HuArgI(Co)] coupled with polyethylene glycol 5000 [HuArgI (Co)-PEG5000]. Cytotoxicity of [HuArgI (Co)-PEG5000] was tested on two GBM cell lines, namely A172 and U251. Both cell lines showed increased sensitivity at longer incubation periods of [HuArgI (Co)-PEG5000] treatment with IC50 values in the pM range, a result attributable to the arginine auxotrophy expressed in those two cell lines. The addition of chloroquine, an autophagy inhibitor, increased the sensitivity of cells to [HuArgI (Co)-PEG5000]-mediated arginine depletion at earlier time points. We also concluded that autophagy was activated in response to arginine depletion and plays a protective role at early time points. However, the excessive accumulation of intracellular autophagosomes upon treatment with chloroquine at later time points illustrates the role of autophagy in response to [HuArgI (Co)-PEG5000]-mediated arginine depletion resulting in ultimate cell death by autophagy. Overall, in this study we showed how arginine auxotrophy in GBM could be used to target such cells through HuArgI (Co)-PEG5000. Hence, HuArgI (Co)-PEG5000 is an efficient and selective therapeutic method for targeting GBM.