Mannose synergizes with chemoradiotherapy to cure cancer via metabolically targeting HIF‐1 in a novel triple‐negative glioblastoma mouse model

Abstract

The standard care of glioblastoma multiforme (GBM), which is surgery followed by temozolomide concurrent radiotherapy (RT/TMZ), confers limited survival benefit for patients. 1 Additionally, current animal models do not faithfully recapitulate human GBM features, impeding animal-to-human translation. 2 Here, we developed and characterized a novel orthotopic murine GBM model, in which we tested the efficacy of the RT/TMZ supplemented with mannose (RT/TMZ/Man). Following the optimized protocol illustrated in Figure 1A, we established a stable subcutaneous-intracranial G422-GBM syngeneic mouse model system. Subcutaneous injection of 1 × 10 6 fresh G422 cells led to 100% tumor formation, and the tumors reaching 1 cm 3 on day 7-9 postimplantation (p.i.) were used for further experiments (Figure 1B). Microinjection of 1 × 10 3-1 × 10 5 G422 cells in mouse striatum caused 100% lethality within 30 days (Figure 1C) and 5 × 10 4 cells, which led to mouse death within 14-23 days (Figure S1A), were selected for establishing the orthotopic model. We then determined the pathology and molecular characters of G422-tumors. The brain slices showed rapid G422-tumor development during day 7-15 p.i. (Figure S1B). The G422tumors were GFAP + Vimentin + CD3 − and infiltrated into distant brain areas (Figure 1D-G) on day 5 p.i. They were IDH1/2 WT chromosome1/19 Intact TERT-promoter WT with ATRX Mutant and Trp53 Mutant (Figure 1H), determined by the whole genome sequencing, and thus belonged to the triple-negative (TN) primary GBM subtype. 3 Our model was therefore named the G422 TN-GBM. Next, we determined the therapeutic responses of the orthotopic G422 TN-GBM to conventional surgery, radiotherapy, temozolomide, and the therapies of combining these two or three. Surgery alone, performed on day 7 p.i., effectively removed the tumor and slightly extended the median survival of the G422-mice (Figure 2A-C and This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Mannose Treatment: A Promising Novel Strategy to Suppress Inflammation

“…For example, it is necessary to calculate the ideal dose of mannose treatment for human inflammation, determine how mannose increases FAO in CD4+ T cells, and whether or not mannose can affect functions of CD8 + T cell and other immune cells. Moreover, since it was also reported that mannose treatment could enhance cancer chemokine therapy ( 52 , 53 ), whether mannose mediated immune responses are involved during this process is totally unknown. Nevertheless, although there are still a number of key questions need to be figured out, the great therapeutic promise of mannose treatment has been disclosed.…”

Mannose inhibits the growth of prostate cancer through a mitochondrial mechanism

“…Mannose has shown potential therapeutic properties in a variety of cancers. 10 11 12 We found that mannose can inhibit the growth of PCa cells. Furthermore, mannose can regulate metabolic reprogramming of osteosarcoma cells.…”

Mannose and phosphomannose isomerase regulate energy metabolism under glucose starvation in leukemia

“… 13 Recently, mannose was reported to be effective against lung cancer, breast cancer, and osteosarcoma. 28 , 29 , 30 , 31 , 32 Low expression of PMI makes cells more sensitive to the antitumor effect of mannose, and all of these cancers express low levels of PMI. By contrast, leukemia cells express PMI, but it remains unclear how mannose metabolism contributes to their survival and proliferation.…”