So simple mannose can inhibit tumor growth

Many tumors have metabolic changes, especially increased glucose uptake [1]. Glucose is a form of hexose (monosaccharide), so does the tumor have a similar response to other members of the hexose family? 

The Kevin Ryan team from Cancer UK answered the question on Nov. 22, 2018, and the study was published in the journal Nature under the title: Mannose impairs tumour growth and enhances chemotherapy [2].

D-Mannose.Photo: https://commons.wikimedia.org/wiki/File:D-Mannose.svg

The researchers first examined the effects of different types of hexose, including Mannose, Galactose, Fructose, Fucose, and Glucose, on the growth of different tumor cell lines (25 nM),). Mannose showed significant inhibitory effects (Fig. 1).

Fig. 1: the effect of different monosaccharides on the growth of different tumor cell lines, of which mannose has the most significant inhibitory effect on the growth of tumor cell lines.

The transporters involved in mannose in cells are the same as glucose (Fig. 2), so does mannose uptake affect glucose uptake? 

With this in mind, the researchers first found that mannose can increase the phosphorylation level of AMPK. It was found that mannose increased Hexoses-6-phosphate, whereas mannose did not affect glucose uptake, but increased intracellular glucose content, a phenomenon that does not exist in other hexoses.

Fig. 2: metabolic pathways of mannose and glucose

Since mannose does not affect glucose uptake, how does mannose affect tumor cell growth? 

The researchers found that mannose-6-phosphate inhibited three enzymes involved in glucose metabolism: hexokinases,phosphoglucose isomerase (PGI) and glocose-6-phosphate dehydrogenase, which in turn affected the tricarboxylic acid cycle, the pentose phosphate pathway, and the synthesis of glycans. The same metabolic inhibition does not exist in other monosaccharides. It is concluded that mannose uptake can affect intracellular glucose metabolism. 

Since mannose can affect the growth of tumor cells by inhibiting the metabolism of glucose, can mannose affect the response of tumor cells to chemotherapeutic drugs? 

Experiments have shown that mannose does increase the apoptosis of tumor cells induced by cisplatin or adriamycin, whereas other hexose does not. Furthermore, by using CRISPR-Cas9 method, the researchers found that the above mannose affects apoptosis through the endogenous pathway of BAX and BAK. 

All of the above experiments were carried out using tumor cell lines in vitro, so does mannose have the same effect in vivo? 

The researchers used in vivo tumorigenic experiments to construct tumor-bearing mice, and then administered mannose to the tumor-bearing mice through feeding tubes (three times a week) and drinking water (continuously). They found that mannose did not affect the weight and health of the mice. But it can significantly inhibit the growth of tumors. In addition, in vivo mannose increased the anticancer effect of adriamycin and significantly prolonged the survival of mice (Fig. 3).

Fig. 3: in vivo mannose can inhibit tumor growth, increase the anticancer effect of adriamycin and prolong the survival time of mice.

Whether in vitro or in vivo, mannose showed a significant anti-cancer effect, so is there a similar effect in all tumors? Since mannose can affect metabolism, is there an enzyme involved in glucose metabolism that is associated with the anti-cancer effect of mannose? 

The researchers found that PMI (the enzyme that catalyzes the conversion of mannose-6-phosphate and fructose-6-phosphate) into each other, phosphomannose isomerase) [1], was negatively correlated with mannose sensitivity. The researchers then knocked down MPI (the gene that encodes PMI) in three tumor cell lines (SKOV3,RKO and IGROV1) that were not sensitive to mannose and found that growth was inhibited after mannose treatment. Apoptosis was increased when mannose and chemotherapeutic drugs were co-treated. On the contrary, overexpression of MPI in mannose-sensitive cell lines could significantly inhibit the effect of mannose. 

Does MPI have the same reaction in the body? The researchers then demonstrated that MPI knockout cells did increase sensitivity to mannose using tumorigenic experiments in mice and in vivo. 

Next, the researchers used tissue chip methods to detect the expression of PMI in different human tumors, including ovarian, renal, breast, prostate, and colorectal cancer, and found that the expression of PMI varied from tumor to tumor. At the same time, even the same tumor expression is also different. The expression of PMI is the lowest in colorectal cancer, which suggests that colorectal cancer may be sensitive to mannose. So the researchers treated two colorectal cancer mouse models with mannose and found that tumor growth was significantly inhibited. 

Overall, the study showed that taking monomanose alone or in combination with chemotherapeutic drugs can inhibit tumor growth.Mannose therapy may be a simple and safe way to target tumor growth. However, further research is still needed to verify this. 

It is worth mentioning that an article published on the Nature Medicine in July last year by Professor Chen Wanjun, a Chinese scientist at the US National Institutes of Health, showed that D- mannose can regulate regulatory T cell (Treg) and inhibit autoimmune diseases [4].

Reference. 

  • 1. Pavlova, N. & Thompson, C. B. The emerging hallmarks of cancer metabolism. Cell Metab. 23,27-47 (2016). 
  • 2. Pablo Sierra Gonzalez & Kevin M. Ryan. Mannose impairs tumour growth and enhances chemotherapy. Nature. (2018). 
  • 3. Sharma, V., Ichikawa, M. & Freeze, H. Mannose metabolism: more than meets the eye. Biochem. Biophys. Res. Commun. 453,220-228 (2014). 
  • 4. Zhang, D., Chia, C., Jiao, X., Jin, W., Kasagi, S., Wu, R.,. & Chen, Q. (2017). D-mannose induces regulatory T cells and suppresses immunopathology. Nature medicine, 23 (9), 1036.
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