D-Mannose Slows Glioma Growth by Modulating Myeloperoxidase Activity

SIMPLE SUMMARY: Inflammation and oxidative stress are important host defense responses. However, while the host response can be cytotoxic and kill tumor cells, tumor cells can also alter and exploit the host immune environment to further their survival. Thus, the host response can impact both tumor suppression and progression. Modulating the tumor–host response interaction to favor tumor suppression would be highly desirable. D-mannose has been found to have anti-inflammatory properties and can block signaling related to myeloperoxidase (MPO), a highly oxidizing pro-inflammatory enzyme secreted in host defense. However, the effect of D-mannose on host immune response in the glioma microenvironment has not been explored. We found that D-mannose slowed glioma growth by increasing MPO activity and oxidative stress in the glioma microenvironment. Our findings revealed that D-mannose may be able to shift the host immune response toward tumor suppression and could be a potential new therapeutic direction for these difficult-to-treat tumors. ABSTRACT: Host immune response in the tumor microenvironment plays key roles in tumorigenesis. We hypothesized that D-mannose, a simple sugar with anti-inflammatory properties, could decrease oxidative stress and slow glioma progression. Using a glioma stem cell model in immunocompetent mice, we induced gliomas in the brain and tracked MPO activity in vivo with and without D-mannose treatment. As expected, we found that D-mannose treatment decreased the number of MPO(+) cells and slowed glioma progression compared to PBS-treated control animals with gliomas. Unexpectedly, instead of decreasing MPO activity, D-mannose increased MPO activity in vivo, revealing that D-mannose boosted the MPO activity per MPO(+) cell. On the other hand, D-glucose had no effect on MPO activity. To better understand this effect, we examined the effect of D-mannose on bone marrow-derived myeloid cells. We found that D-mannose modulated MPO activity via two mechanisms: directly via N-glycosylation of MPO, which boosted the MPO activity of each molecule, and indirectly by increasing H(2)O(2) production, the main substrate for MPO. This increased host immune response acted to reduce tumor size, suggesting that increasing MPO activity such as through D-mannose administration may be a potential new therapeutic direction for glioma treatment.