Anti-cancer potential of arginase for high-grade glioma in vitro & in-vivo

Abstract

Background: High-grade glioma is currently incurable. It was reported that glioma may be auxotrophic to arginine due to the lack of urea cycle genes expressions, suggesting arginase may be a potential agent for high grade glioma. Aim: We investigated the efficacy of pegylated arginase I (pegArg-I) or in combination with other anti-cancer drugs for high-grade glioma in vitro and in vivo. Methods: 4 high-grade glioma cell lines (U87, U373, U138, D54) were treated with pegArg-I in vitro. The molecular mechanism of pegArg-I-induced cytotoxicity was tested in U87. The ultra-morphological changes of pegArg-I-treated U87 was investigated by both scanning and transmission electron microscopy. Orthotopic glioma xenograft model with luciferase-transfected U87 cell line was tested for anti-cancer efficacy of peg-Arg I in vivo. Results: We showed that pegArg-I induced significant cell death in all 4 cell lines in vitro. Temozolomide, difluoromethyornithine and chloroquine (CQ) were then tested together with pegArg-I in U87 in vitro. We found that only CQ showed additive effect with pegArg-I against glioma in vitro. Such additive cytotoxic effect may be associated with enhanced autophagy and necrosis as shown in transmission electron microscopy and autophagy markers’ expression by Western blotting. PegArg-I prolonged the survival of glioma mice, suggesting its possible anti-glioma efficacy. However, CQ+pegArg-I didn’t show further significant anti-cancer efficacy in vivo. Conclusion: PegArg-I may be useful in slowing the progression of glioma, but additional drug candidate which works synergistically with pegArg-I remains to be explored.