Mannose Inhibits the Pentose Phosphate Pathway in Colorectal Cancer and Enhances Sensitivity to 5-Fluorouracil Therapy

SIMPLE SUMMARY: 5-fluorouracil (5-FU) has been the treatment of choice against colorectal cancer (CRC) for the past six decades. However, 5-FU exhibits high toxicity and drug resistance in CRC patients, highlighting the need for less toxic and more efficient treatments. The pentose phosphate pathway (PPP) is upregulated in cancer cells and promotes their survival. Recently, mannose has been reported to halt tumor growth and impair the PPP. We studied the effect of mannose, alone and in combination with 5-FU in human CRC cells and animal models. We have shown that mannose alone or in combination with 5-FU downregulated the PPP and enhanced the sensitivity of CRC cancer cells and tumors in mice to 5-FU. Therefore, this research may pave the way for better patient care. ABSTRACT: Colorectal cancer (CRC) is one of the leading cancers and causes of death in patients. 5-fluorouracil (5-FU) is the therapy of choice for CRC, but it exhibits high toxicity and drug resistance. Tumorigenesis is characterized by a deregulated metabolism, which promotes cancer cell growth and survival. The pentose phosphate pathway (PPP) is required for the synthesis of ribonucleotides and the regulation of reactive oxygen species and is upregulated in CRC. Mannose was recently reported to halt tumor growth and impair the PPP. Mannose inhibitory effects on tumor growth are inversely related to the levels of phosphomannose isomerase (PMI). An in silico analysis showed low PMI levels in human CRC tissues. We, therefore, investigated the effect of mannose alone or in combination with 5-FU in human CRC cell lines with different p53 and 5-FU resistance statuses. Mannose resulted in a dose-dependent inhibition of cell growth and synergized with 5-FU treatment in all tested cancer cell lines. Mannose alone or in combination with 5-FU reduced the total dehydrogenase activity of key PPP enzymes, enhanced oxidative stress, and induced DNA damage in CRC cells. Importantly, single mannose or combination treatments with 5-FU were well tolerated and reduced tumor volumes in a mouse xenograft model. In summary, mannose alone or in combination with 5-FU may represent a novel therapeutic strategy in CRC.