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Mannose and Cancer

I’m always happy to see something show up in the research literature that can be immediately applied in clinical practice. Working in drug discovery, you get used to everything maybe having an impact years in the future, if everything works out (and it rarely does!) So when you see an actionable idea that applies to current therapy, it seems a bit magical.

Here’s something in that category: a multicenter team led out of Glasgow reports that mannose can have a real effect on chemotherapy. It’s well known that many tumor types have enhanced uptake of glucose (this is tied in to the Warburg effect, the use of aerobic glycolysis as an energy pathway). The authors of this new paper have been looking at the effects of various monosaccharides on this process, and it turns out that mannose is the most effective. It’s taken up by the same transport proteins as glucose, but once in the cell it piles up as mannose-6-phosphate, and this impairs glycolysis and several other glucose-based pathways.

The team demonstrated this first in the U2OS cell line, and extended it to mouse models. When the animals were dosed with mannose, tumor growth seemed to be significantly impaired. And (even more relevant to human therapy), mannose supplementation seemed to make chemotherapy (doxorubicin or cisplatin) more effective, presumably because the tumor cells were already under stress from having their metabolism interfered with. The mannose treatment increased cell death through apoptosis, with further knockdown experiments showing that this is almost certainly through the intrinsic pathway rather than the extrinsic one. That makes sense – the intrinsic pathway involves the mitochondria, which is what you’d expect if you’re going after glucose-based metabolic pathways.

The paper goes on to find a potential biomarker for which tumor types will be most sensitive to this treatment. Phosphomannose isomerase (PMI) is the key: cell lines with high levels of the enzyme are resistant to the effects of mannose, because the enzyme converts mannose-6-phosphate to fructose-6-phosphate, which can then enter the glycolysis pathways. Cells with low PMI levels, though, are stuck. You can, in fact, turn resistant cells into sensitive ones by knocking down PMI, and take sensitive ones (such as the U2OS line that kicked off the study) into resistant ones by overexpressing it, which seems pretty definitive. Looking over tissue samples, it appears that colon cancer lines are particularly deficient in PMI, whereas ovarian, renal, breast, and prostate samples showed much more variable expression and cell-to-cell heterogeneity. The paper shows that mice with an induced colon-cancer phenotype have significantly fewer tumors when their water supply is supplemented with mannose, and there seemed to be no ill effects from the treatment.

So that would be the place to start. Mannose is not known to be a problem for humans, either, so I would say that physicians treating patients with colorectal cancer would be well advised to give it a try. I look forward to controlled data on this idea, but for now the risk/reward looks very favorable.


19 comments on “Mannose and Cancer”

  1. John Adams says:

    Question: why would this be approach superior to 2-deoxy-D-glucose? Reduced toxicity to non-transformed cells?

    1. Derek Lowe says:

      See the Extended Data in the paper, Figure 10g. 2-deoxyglucose cause ER stress, while mannose doesn’t. . .

  2. Project Osprey says:

    Sounds like mannose from heaven to me.

    1. Some idiot says:

      NI’ve…! 🙂

  3. 42 says:

    I sense a new wave of “superfoods” are inbound.

  4. MrRogers says:

    Interesting, but I’m surprised it’s getting so much interest. I note that in the figures there’s little evidence for tumor shrink. In Figure 3, you get at best stable disease at 40 days (no indication what happens after that) and a lifespan extension of about 3 weeks (~25%). Figure 4i (Mannose + shPMI–presumably as a stand-in for a PMI inhibitor) shows similar results in B16F1. Only with LLC-shPMI is long-term disease stabilization observed. (It’s also interesting that even in the absence of mannose, LLC-shPMI grows much slower than any LLC I’ve ever worked with.) I’d say this paper is interesting primarily because it suggests that PMI antagonists should be developed. I’d be shocked if mannose shows activity by itself. Fortunately, it’s cheap enough that we should know soon.

    1. loupgarous says:

      PMI antagonists should be developed, just on general principles, but mannose could still have a role even in things like biologic therapy for tumors. One of the things that makes everolimus an anti-cancer drug is its inhibition of glycolysis in tumors (if I’m reading the literature right). The side effect I and some others who used it had, significant fasting hyperglycemia, may confirm that.

      If people who can tolerate everolimus get mannose supplemenation in their diet, could this cause tumor cell death at a higher rate? Is it worth checking out? Mannose might be a rare non-toxic adjuvant in cancer chemotherapy.

  5. RTW says:

    This might be difficult in practice to implement initially as the first line treatment is with the FOLFOX protocol using 5-FU, Oxaliplatin and Leucovorin IV. The protocol starts with IV Oxaliplatin which is in a solution of Dextrose (D5W) infused over a period of 2 hrs followed by Leucovorin in saline or D5W IV over 2 hours followed by 5-FU usually in Saline or (usually D5W).

    So unless they reformulate these three drugs the use of Mannose probably wont be effective as I bet the dextrose will rescue the tumor mitochondria. This would require a big shift in manufacturing at this point, or the need for a lot more pharmacy techs to custom formulate this in Mannose solution at infusion centers. Sometimes (more so today than 5 years ago) they Add Avastin to this cocktail. The second line treatment is FOLFIRI swap in Irinotecan for Oxaliplatin, again with and without Avastin, and then there is somethin called FOLFIRINOX, or FOLFOXIRI slightly different protocol with the same drugs. Additionally based on genetic screening test they might use Erbitux.

    I really wish this study was done 5 or more years ago – It could have perhaps saved my wife.

    1. In Vivo Veritas says:

      I’m really surprised that coformulation with mannose was not explicitly recommended. The only downside is that the agency might want a clinical safety trial on the new formulation – but I believe that an IV formulation of mannose already exists, so you might get a pass on that….
      Keep in mind that if some scumbag starts selling Oxaliplatin in mannose at 10x the price of the standard formulation, it’s not me. :\

  6. serine says:

    I do not see how would one can deprive the cancer of glucose and feed it with Mannose when there is glucose circulating in blood though your chemotherapeutic are formulated in Mannose. I am sure missing something here.

    1. Derek Lowe says:

      The mannose phosphate builds up in the cells over time, and the tumor cells are more sensitive to its effects. They also take up more of the mannose, since they’re already taking in more glucose, and it’s the same transport mechanism.

  7. JB says:

    Mannose is also a precursor for fucose. Abberrant fucosylation is a well known phenomena for many types of aggressive cancers with poorer prognoses. I wouldn’t doubt at all if tumors were also addicted to mannose for other reasons besides those direclty related to metabolism.

  8. WH says:

    If glucose promotes tumors, why does one get a 5 L solution (can’t remember the concentration) every day after BEP treatment? Sure it’s for flushing, but couldn’t that be done with saline? Or mannose?

  9. I’m joining dots here, but mannose is known to have a fairly profound effect on gut microbiome composition (with a potentially beneficial effect on metabolism). Certain gut bacteria, such as sulfidogenic bacteria, are associated with colorectal cancer risk.

    I’d hope that the enhanced drug sensitivity observed with tumour lines and mouse models holds true in clinical studies, but can’t help but wonder whether, at least in some individuals, microbiome-related tumour promotion (or protective effects) might be adversely altered by a high mannose diet.

  10. Richard Bernstein says:

    I worked in the laboratory of Efraim Racker at Cornell. He was ridiculed for studying the biochemistry of the Warburg effect and thought oncogenes might have something to do with this effect. Turns out he wasn’t so stupid! I hope he’s looking down with joy from biochemistry heaven.

  11. André Pilot says:

    Mannose looks to be an interesting way to reduce or limit cancer propagation. Do you know if there is any hospital that is taking these results into account and that are changing their protocoles to include Mannose?
    Do you know if there is any recommandation / any protocole / any trial in progress on that? I have seen nothing specific yet on that.

  12. Doug Jones says:

    In connection with the glucose metabolism of cancers, there’s this evidence suggesting that ketogenic diets are also useful for cancer patients:

    It seems likely that a keto diet with mannose supplements would be more effective than either alone (and of course in conjunction with chemotherapy).

  13. Leonid Makar-Limanov says:

    Any idea about the dose which (may be) effective?

    1. André PILOT says:

      I have made some conversion assuming we use a DHE mouse / human of 0,081.
      0,2 ml / 0,020 kg (mouse) * 0,081 = 0,81 ml/kg (human)
      For a 50 kg human : 0,81 ml/kg x 50 kg = 40,5 ml each time.

      a w/v% of 20% means 0,2 * 1kg/liter = 200 g/l = 0,2 g/ml

      so : 40,5 ml each time * 0,2 g/ml = 8 g each time
      Was givent to mouse 3 times per week. Overall, in a week : 3 x 8 = 24 g of mannose for a 50 kg person. (to be compared to some recommandations for cystites : 26 g per week)

      These are my computations.

      To you have any news regarding application made on human?

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