Autophagy suppression potentiates the anti-glioblastoma effect of asparaginase in vitro and in vivo

Abstract

Asparaginase has been reported to be effective in the treatment of various leukemia and several malignant solid cancers. However, the anti-tumor effect of asparaginase is always restricted due to complicated mechanisms. Herein, we investigated the mechanisms of how glioblastoma resisted asparaginase treatment and reported a novel approach to enhance the anti-glioblastoma effect of asparaginase. We found that asparaginase could induce growth inhibition and caspase-dependent apoptosis in U87MG/U251MG glioblastoma cells. Meanwhile, autophagy was activated as indicated by autophagosomes formation and upregulated expression of LC3-II. Importantly, abolishing autophagy using chloroquine (CQ) and LY294002 enhanced the cytotoxicity and apoptosis induced by asparaginase in U87MG/U251MG cells. Further study proved that Akt/mTOR and Erk signaling pathways participated in autophagy induction, while reactive oxygen species (ROS) served as an intracellular regulator for both cytotoxicity and autophagy in asparaginase-treated U87MG/U251MG cells. Moreover, combination treatment with autophagy inhibitor CQ significantly enhanced anti-glioblastoma efficacy of asparaginase in U87MG cell xenograft model.Taken together, our results demonstrated that inhibition of autophagy potentiated the anti-tumor effect of asparagine depletion on glioblastoma, indicating that targeting autophagy and asparagine could be a potential approach for glioblastoma treatment.

Efficacy of Asparaginase Erwinia chrysanthemi With and Without Temozolomide Against Glioma Cells and Intracranial Mouse Medulloblastoma

“…We reported in 2013 that the anti-leukemia agent E. coli-ASNase enhances chemo-cytotoxicity against brain tumors (20). Additional studies validating the antiglioblastoma activity of ASNase in vitro and in vivo were recently reported (33,34). Our current study shows that activity of Erwinaze against brain tumor cells is comparable to the reported in vitro effects of E. coli-ASNase ( Figure 1A and 4).…”

Targeting autophagy potentiates the anti-tumor effect of PARP inhibitor in pediatric chronic myeloid leukemia

“…Autophagy is an evolutionarily conserved cellular process, which plays an important role in tumor microenvironment (Zhang et al 2018b). Many anti-tumor agents, including asparaginase, arginase, cisplatin and immune checkpoint inhibitor, activated autophagy in cancer cells (Chen et al 2017; Shen et al 2017; Zhang et al 2018a). Blocking autophagy significantly increased the anti-tumor effect of these agents, demonstrating that autophagy could be an efficient target to enhance the efficacy of anti-tumor regents.…”

Amino Acid Degrading Enzymes and Autophagy in Cancer Therapy

“…The high immunogenicity and shorter half-life may be the greatest obstacles in the development of drugs ( Schiffmann et al, 2019 ; Thisted et al, 2019 ). Chemical modification, construction of fusion protein, and encapsulation of enzymes are some of the existing solutions to overcome those obstacles and increase the bioavailability of amino acid degrading enzymes ( Veronese, 2001 ; Li et al, 2007 ; Chen and Zeng, 2016 ; Bilal et al, 2018 ; Sinha and Shukla, 2019 ).…”

“…Also, autophagic flux was observed in TNBC cells. Blocking autophagy by CQ, 3-MA and silencing Beclin1 enhanced the antitumor effect of rhArg in TNBC ( Wang et al, 2014a ). Until now, rhArg was also found to have an inhibitory effect on melanoma cells ( Wang et al, 2014b ), non-Hodgkin’s lymphoma cells ( Zeng et al, 2013 ), laryngeal squamous cell carcinoma cells ( Lin et al, 2015 ), leukemia cells ( Li et al, 2016 ), ovarian cancer cells ( Nasreddine et al, 2020 ), and non-small-cell lung cancer (NSCLC) cells ( Shen et al, 2017 ).…”