LONDON—A recent study funded by Cancer Research UK and Worldwide Cancer Research has found a new aspect to the relationship between cancer and glucose: a certain kind of sugar can actually impede cancer growth. The results appeared in Nature in a paper titled “Mannose impairs tumour growth and enhances chemotherapy.”
The key to this discovery is the sugar monomer mannose, a nutritional supplement that is sometimes used as a treatment for urinary tract infections. Mannose, according to a Cancer Research UK press release, “is taken up by the same transporter as glucose and impairs glucose metabolism.” Glucose and mannose share a similar structure, as both are members of the same family.
Their effects, however, are rather different. In this research, mice with pancreatic, lung or skin cancer were administered mannose via their drinking water and as an oral treatment, which led to significantly slower tumor growth. When administered three times a week, tumor growth halted. The researchers determined that mannose works by interfering with the metabolism of glucose in cancerous cells.
“Mechanistically, mannose is taken up by the same transporter(s) as glucose but accumulates as mannose-6-phosphate in cells, and this impairs the further metabolism of glucose in glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway and glycan synthesis,” the authors explained in their abstract. “As a result, the administration of mannose in combination with conventional chemotherapy affects levels of anti-apoptotic proteins of the Bcl-2 family, leading to sensitization to cell death.”
Prof. Kevin Ryan, lead author from the Cancer Research UK Beatson Institute, said that: “Tumors need a lot of glucose to grow, so limiting the amount they can use should slow cancer progression. The problem is that normal tissues need glucose as well, so we can’t completely remove it from the body. In our study, we found a dosage of mannose that could block enough glucose to slow tumor growth in mice, but not so much that normal tissues were affected. This is early research, but it is hoped that finding this perfect balance means that, in the future, mannose could be given to cancer patients to enhance chemotherapy without damaging their overall health.”
The team also explored whether mannose impacts chemotherapy by treating mice with cisplatin and doxorubicin, two of the most common chemotherapy drugs, and giving them mannose supplements. This was found to boost the effectiveness of chemotherapy, as the mice saw slower tumor growth and a reduction in tumor size, with some mice even experiencing longer lifespans.
The effects are not uniform across all cancer types, however; when the scientists investigated mannose's effects in other cancer types—such as leukemia, osteosarcoma, ovarian and bowel cancer—they saw that responses varied. Ryan said in a press release that “Our next step is investigating why treatment only works in some cells, so that we can work out which patients might benefit the most from this approach. We hope to start clinical trials with mannose in people as soon as possible to determine its true potential as a new cancer therapy.”
According to the Nature paper, “[S]usceptibility to mannose is dependent on the levels of phosphomannose isomerase (PMI). Cells with low levels of PMI are sensitive to mannose, whereas cells with high levels are resistant, but can be made sensitive by RNA-interference-mediated depletion of the enzyme. In addition, we use tissue microarrays to show that PMI levels also vary greatly between different patients and different tumour types, indicating that PMI levels could be used as a biomarker to direct the successful administration of mannose.”
Encouragingly, the administration of mannose doesn't seem to adversely impact normal cells, as Ryan noted in a blog post by Cancer Research UK’s Lily Almeida that “Taking mannose did not significantly affect the weight or health of the mice. However, our study didn’t do a detailed analysis of every tissue, so it is not certain that mannose is completely safe.”
He also cautioned that “While there is promise for future treatments involving mannose, it would be very inadvisable for cancer patients to start using it now. Cancer patients taking mannose for a long period of time that are likely to have weakened immune systems from cancer treatment are not the same as people using mannose in the short-term for UTIs.”
Other recent Cancer Research UK-led research explored another angle of the relationship between cancer and glucose, and whether it can be safely exploited. A team of scientists led by Arthur Dyer, lead author and a Cancer Research UK-funded Ph.D. student from the University of Oxford, published their results on how interfering with how cancer cells metabolize glucose could help oncolytic viruses better attack tumors.
“When studying any kind of drug in the lab, we keep the cells in very high sugar conditions—it’s a bit like soaking them in Lucozade,” Dyer explained in a press release. “But this doesn’t reflect the conditions that these cells would be exposed to in the body, which are normally much poorer; in cancer they’re even worse because tumors typically have poor circulation. Our approach is more realistic in mimicking the conditions in the human body, which ultimately may help us to better predict how patients will respond to drugs well before any trials are planned.”
Lung, ovarian and colon cancer cells, along with mouse models, were exposed to conditions more closely resembling those in the human body, then challenged with an oncolytic virus. The scientists discovered that these viruses are more effective in low-glucose environments. By treating cells with 2-deoxyglucose, a drug that inhibits cancer cells' ability to metabolize glucose, an oncolytic virus was able to multiply much faster than usual due to the resulting low sugar levels which boosts its effectiveness.
“By making treatments work more effectively, we hope that patients will be able to see positive results faster than before. The next step is to test whether this approach works in clinical trials, and to find out which cancers respond best,” remarked Dr. David Scott, Cancer Research UK’s director of discovery research.