D-MANNOSE

D-Mannose is known for its antibacterial and antiinflammation actions, particularly in managing urinary tract infection. Emerging lab research points to some promise as an adjuvant to chemotherapy treatments, including colorectal, glioma and breast cancer. There is quite good evidence of how and why mannose reduces tumor cells access to glucose.

More recent pre-clinical testing has shown possible applications during radiotherapy and immunotherapy including with trametinib used for melanoma and glioma. These findings might be verified in patient studies, though dosage levels that can be tolerated during oncology treatments maybe a limiting factor.

Elevated mannose levels sustained over time are indictators of insulin resistance and linked to diabetes, so the potential benefits are in specific treatment windows.

TYPICAL ABSORPTION LEVELS

20 – 30%

EXAMPLES OF IMPROVED OUTCOMES

PENDING

PRE-DIAGNOSIS OR PREVENTION

NO

Highlighted Studies

It was observed [in a mouse model] that while both doxorubicin and mannose individually caused a reduction in tumor volume, doxorubicin could also act synergistically when administered in combination with mannose. Notably, when the authors investigated the overall survival period of the treated cohorts, the subjects treated with both mannose and doxorubicin had significantly increased life expectancy.

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..our study established a functional link between a metabolite and immune evasion and uncovered an unknown effect of D-mannose on immunotherapy and radiotherapy of TNBC. The findings of this study pave the way for the potential use of D-mannose in the clinical treatment of TNBC.

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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… administration of mannose could be a simple, safe and selective therapy in the treatment of cancer, and could be applicable to multiple tumour types.

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Notably, combination of d-mannose and PD-1 blockade exhibits remarkable tumor growth suppression attributed to elevated cytotoxicity activity of T cells in vivo. Furthermore, d-mannose treatment dramatically improves the therapeutic efficacy of MEK inhibitor (MEKi) trametinib in vivo. Our findings unveil a universally unrecognized anti-tumor mechanism of d-mannose by destabilizing PD-1 and provide strategies to enhance the efficacy of both immune checkpoint blockade (ICB) and MEKi -based ther...

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TABLE OF REFERENCES

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https://www.jstage.jst.go.jp/article/tigg/31/180/31_1963.6E/_pdf1Subsequently, to inves- tigate whether mannose can enhance the effects of chemotherapy, tumor-bearing nude mice were treated with mannose or doxorubi- cin either alone or in combination. It was observed that while both doxorubicin and mannose individually caused a reduction in tumor volume, doxorubicin could also act synergistically when admin- istered in combination with mannose. Notably, when the authors investigated the overall survival period of the treated cohorts, the subjects treated with both mannose and doxorubicin had signifi- cantly increased life expectancy.Taken together, mannose has the potential to become a univer- sal remedy. Mannose is available as a supplement and is expected to exhibit a few side effects even if administered for a long period. The authors also showed that the serum concentration of mannose was approximately 3 mM after mannose administration. In humans, the physiological serum mannose concentrations can reach approx- imately 1 mM. Hence, due to the abundance of mannose in fruits such as cranberries, it is likely that the ingestion of these fruits might delay the disease progression of cancer.
http://eprints.gla.ac.uk/170784/7/170784.pdf1In contrast to the effects on glucose metabolism, mannose does not decrease amino acid or fatty acid uptake and while mannose reduces glucose-dependent serine and glycine synthesis, this contributes only marginally to total cellular serine and glycine pools (Extended Data Fig. 10a-f). Mannose also affects transcription, translation and autophagy, but these effects were reversed by PMI over-expression, indicating they are downstream of glucose metabolism (Extended Data Fig. 10g-l). Moreover, ablation of autophagy did not affect mannose sensitivity showing that autophagy inhibition is not the mechanism underlying the effects of the sugar (Extended Data Fig. 10m,n). In summary, we conclude that mannose represents a well-tolerated means to interfere with glucose metabolism that could potentially be used clinically either alone or in combination with other forms of cancer therapyWe were also interested to know if mannose can also enhance chemotherapy in vivo. Tumour-bearing nude mice were therefore treated with mannose and doxorubicin either alone or in combination. While none of the treatments affected the weight or visible health of the animals (Extended Data Fig. 6h), we found that either doxorubicin or mannose caused a reduction in tumour volume (Fig. 3c). Moreover, when doxorubicin was administered in combination with mannose an even greater effect was observed (Fig. 3c). Importantly, when we examined the overall survival of the treated cohorts, those treated with doxorubicin plus mannose had a significantly increased life expectancy when compared to untreated mice or those treated with either doxorubicin or mannose alon
https://www.nature.com/articles/s41586-018-0729-31We consider that the administration of mannose could be a simple, safe and selective therapy in the treatment of cancer, and could be applicable to multiple tumour types.we report that the monosaccharide mannose causes growth retardation in several tumour types in vitro, and enhances cell death in response to major forms of chemotherapy. We then show that these effects also occur in vivo in mice following the oral administration of mannose
https://www.sciencedirect.com/science/article/abs/pii/S01970186220007301In this study, xenograft glioma model and glioma cell lines were used to study the function of mannose in TMZ efficacy and the underlying mechanism was also explored. We illustrated that mannose inhibited the proliferation of glioma through downregulating PMI and simultaneously reducing MGMT via Wnt/β-catenin signaling, which contributed to improve the sensitivity of TMZ [temozolomide] to glioma. Furthermore, mannose and TMZ inhibited MGMT expression and Wnt/β-catenin activation. Moreover, activating Wnt/β-catenin pathway blocked anti-proliferative effect induced by mannose and TMZ, which was further suppressed by overexpressed MGMT. Mannose inhibited glioma growth, suppressed Ki67 and downregulated MGMT and β-catenin in vivo.
https://pmc.ncbi.nlm.nih.gov/articles/PMC8777573/1Moreover, the inhibitory effect was significant on KYSE450 cell lines with an increased mannose concentration. The application of 11.1 mM/L mannose could significantly enhance the radio-sensitivity of KYSE450 cell line; and tumor cell apoptosis rate was also increased. However, there was limited efficacy of mannose on the radio-sensitivity and apoptosis rate of KYSE70 cell line. Additionally, intracellular metabolites analyzation revealed that glycolysis could be disturbed by mannose when combined with radiation therapy in esophageal cancer cells.down-regulated hypoxia-inducible factors enhanced tumor response to radiation therapy via reducing lactate production and impairing glycolysis [25]. In the present study, we observed mannose contributes to the radiation sensitivity of KYSE450 cell lines; the possible mechanism was that uptake of mannose by glucose transporters drives the accumulation of mannose-6-phosphate, which in turn impairs tumor glycolysis and enhances the efficacy of radiation therapy in cancer patients with low MPI expression.
https://pmc.ncbi.nlm.nih.gov/articles/PMC8656095/1 we demonstrate that mannose selectively kills thyroid cancer cells, and this effect is highly dependent on enzyme activity of PMI rather than its expression. Further studies reveal that PMI can be activated by zinc transport protein ZIP10 through promoting Zn2+ influx, thereby decreasing the response of thyroid cancer cells to mannose. Thus, our data highlight a crucial role of expression status of ZIP10 in affecting the response of thyroid cancer cells to mannose, and offer a mechanistic rationale for exploring clinical use of mannose in thyroid cancer therapy, especially combining with chemotherapy, radiotherapy or immunotherapy.ur data demonstrated that mannose selectively suppressed the growth of thyroid cancer cells, and found that enzyme activity of PMI rather than its protein expression was negatively associated with the response of thyroid cancer cells to mannose. Besides, our data showed that zinc ion (Zn2+) chelator TPEN clearly increased the response of mannose-insensitive cells to mannose by inhibiting enzyme activity of PMI, while Zn2+ supplement could effectively reverse this effect. Further studies found that the expression of zinc transport protein ZIP10, which transport Zn2+ from extracellular area into cells, was negatively related to the response of thyroid cancer cells to mannose. Knocking down ZIP10 in mannose-insensitive cells significantly inhibited in vitro and in vivo growth of these cells by decreasing intracellular Zn2+ concentration and enzyme activity of PMI
https://www.sciencedirect.com/science/article/abs/pii/S03043835240027631Mechanically, d-mannose potentially suppressed PD-1 endocytic recycling, thus promoting its subsequent lysosomal degradation. In the meantime, d-mannose induced phosphorylation of GSK3β at Ser9, thereby leading to GSK3β inactivation and TFE3 translocation to nucleus. Importantly, nuclear TFE3 was responsible for enhanced lysosome biogenesis and subsequent PD-1 proteolysis. Moreover, we showed that d-mannose reduced tumor growth and synergistically enhanced the efficacy of anti-PD-1 therapy in vivo. Notably, combination of d-mannose and MEKi trametinib could dramatically inhibit tumor growth in a KRAS-mutated CT26 mouse model.d-mannose is reported to facilitate immunotherapy and radiotherapy in triple-negative breast cancer (TNBC) by targeting PD-L1 for proteasome-mediated degradation [25], while its effects on other cancer types and other immune checkpoint molecules are still unknown. To explore whether d-mannose affects PD-1 expression level,we evaluated the effects of different hexoses on PD-1 in Jurkat cells ectopically expressing Flag-tagged PD-1. We observed that d-mannose, but not other hexoses, significantly
https://www.pnas.org/doi/10.1073/pnas.2114851119#1D-mannose not only promotes degradation of PD-L1 but also induces abnormal glycosylation of residual PD-L1, both of which suppress the interaction of cell surface PD-L1 with PD-1. Based on these findings, we used D-mannose and anti–PD-1 antibodies to treat TNBC in mice. The results showed that the combination of D-mannose with PD-1 blockade significantly suppressed TNBC growth and dramatically extended the lifespan of tumor-bearing mic Triple-negative breast cancer (TNBC) has the worst prognosis and highest risk of distant relapse in breast cancer and shows resistance to immunotherapy and radiotherapy. In this study, we found that D-mannose can promote the degradation of PD-L1 and significantly enhance immunotherapy and radiotherapy of TNBC. Since TNBC treatment is still a clinical challenge, our findings provide strategies to enhance the therapeutic efficacy of TNBC and may have clinical application.Screenshot from 2024-01-23 22-25-46
https://www.mdpi.com/2072-6694/15/8/226815-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.We noticed a significant decrease in tumor volumes in mice treated with mannose alone or in combination with 5-FU compared to the control group (males and females combined) (Figure 9B). Unexpectedly, the combination treatment of mannose/5-FU did not reduce tumor volumes in treated male mice. Interestingly, male mice showed the most pronounced tumor growth inhibition in the mannose-treated group (Figure 9C), while female mice exhibited a less significant tumor volume reduction (Figure 9D). Female mice showed the most significant tumor volume reduction in the mannose/5-FU combination group (Figure 9D).Screenshot from 2024-11-27 10-21-17
https://pmc.ncbi.nlm.nih.gov/articles/PMC7648561/1The results of animal experiments revealed that the size and weight of tumors derived from A549 cells treated with mannose were smaller than those derived from control cells, and co-treatment with mannose and carboplatin had most efficient inhibition on tumor growth. MPI expression detection showed that the expression level of MPI in the stage Tis (tumor in situ) was the highest, while the stage IV has the lowest.Collectively, our findings suggest that mannose inhibited cell proliferation and migration, promoted cell apoptosis and enhanced the efficacy of carboplatin in lung adenocarcinoma. Preliminary results showed that mannose had less side effect on health. In the future, mannose may be a potential candidate drug for adjuvant therapy of lung adenocarcinoma.Screenshot from 2024-11-27 09-54-43
https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.172301Notable among the metabolic traits in cancer cells is the Warburg effect, which is a reprogrammed form of glycolysis that favors the rapid generation of ATP from glucose and the production of biological macromolecules by diverting glucose into various metabolic intermediates. Meanwhile, mannose, which is the C-2 epimer of glucose, has the ability to dampen the Warburg effect, resulting in slow-cycling cancer cells that are highly susceptible to chemotherapy. This anticancer effect of mannose appears when its catabolism is compromised in cancer cells. Moreover, de novo synthesis of mannose within cancer cells has also been identified as a potential target for enhancing chemosensitivity through targeting glycosylation pathways. The underlying mechanisms by which alterations in mannose metabolism induce cancer cell vulnerability are just beginning to emerge.Apart from the anticancer effects of mannose, this sugar can alleviate the side effects of chemotherapy with oxaliplatin in the small intestine and kidney by inhibiting pyroptosis [[101]], a type of cell death regulated by gasdermin (GSDM) family proteins [[102]]. Mannose suppresses oxaliplatin-induced pyroptosis specifically in normal tissues without affecting the anticancer effects of oxaliplatin [[101]]. This cytoprotective effect of mannose involves AMPK activation. The activated AMPK phosphorylates GSDME protein and interferes with the proteolytic cleavage of GSDME by caspase-3 [[101]], a process that is essential for the induction of pyroptosis. High expression of GSDME in normal cells and its low expression in tumor cells restrict the protective effects of mannose on normal tissues

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