Abstract
This study used in vitro experiments and an orthotopic glioblastoma (GBM) mouse model to test the efficacy of human pegylated arginase I formulation, BCT-100, against the incurable cancer, GBM. Arginine auxotrophy in GBM was verified in silico and in vitro by absence of OTC and ASS1 expression. BCT-100 inhibited growth and induced cell death in four GBM cell lines in vitro. Transcriptomics of U87 and U373 treated with BCT-100 responded differently. BCT-100-treated U87 showed autophagy induction. Cytotoxicity enhancement was observed in four cell lines treated with BCT-100 + chloroquine (CQ). CQ + BCT-100 induced caspase-dependent and caspase-independent cell death in luciferase-transfected U87 (U87(lf+)). BCT-100 or CQ monotherapy, but not BCT-100+ CQ, prolonged survival of intracranial U87(lf+)-bearing mice similarly without suppressing tumor growth. Mouse microglia cell BV2 protected U87(lf+) from BCT100-induced cytotoxicity in transwell co-culture. Etoposide suppressed BV2's protection to U87(lf+) upon BCT-100 treatment by suppressing the growth and inducing cell death of BV2, suggesting microglial suppression as a strategy for enhancing the efficacy of BCT-100. Microglial protection may explain the in vitro and in vivo discrepancies. Further investigation into microglia/GBM interactions may help improve the efficacy of arginine deprivation therapy against GBM.