A combination of vitamin B1/B3/B7 and aspirin, has curative effects on human mantle-cell lymphoma
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@Ismail Final update on this topic...
As promised above, I ran it for about another 30 days. So I did it from May 18 2024 through Aug 24 2024 which is 98 days. I then stepped down dosages over 8 days. I have continued with a daily baby aspirin (81mg) but otherwise the protocol is finished.
The benefits I noted in an earlier post remained through the end of the experiment. I don't believe I posted on this "benefit" but my alcohol tolerance was through the roof and I had no brain fog or other hangover the next day. I don't drink a lot anymore and usually limit myself to 1 or 2 drinks in a whole week; if I do 2 drinks at once I get a hangover. This protocol cured that.
Once I quit the protocol, my energy levels settled at a lower level again. My breathlessness on stair climbs also returned. My alcohol tolerance is worse than it's ever been, so other than a glass of wine once a week with my wife I don't even drink anymore. My favorite cocktails (sidecar, manhattan, gin martini) now make me feel terrible after just 1 of them.
I wish I had better news. At minimum, I'll say this protocol was safe for me but I see little reason to try it again any time soon.
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Hey guys, someone dear to me was recently diagnosed with pancreatic cancer. It's pretty severe with few options moving forward, so I'm going to give this b vitamin and aspirin protocol a try for her. I'm also thinking doxycycline, RU486, baking soda, and vitamin D, and maybe Progest-e and thyroid. Throwing everything at it.
Just wondering if anyone has experimented with this and had any insights overall. I don't want to overload her with a ton of things and cause more stress, but these all seem to be good ideas based on what I've learned here. Any thoughts would be greatly appreciated. Thank you.
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We know from Ray and other authors that thiamin, niacin, and aspirin have therapeutic potential in cancer. It seems that biotin was included in the combination without much consideration, and Jorge had access to more promising options already in his store.
I know that the priority is to nourish the person, but it's most effective when we limit nourishment to cancer cells. Biotin is a vitamin whose anabolic functions prevail, making supplementation a questionable intervention.
The assumption might have been that if pyruvate dehydrogenase (PDH) is inhibited, the alternative means to metabolize pyruvate away from lactate would be with the biotin-dependent pyruvate carboxylase (PC) to oxaloacetate.
Mitochondria are not just energy-producing organelles, they're also biosynthetic sites, with pyruvate carboxylase having an important role in this anabolic picture.
Oxaloacetate can help to export excess mitochondrial acetyl-CoA (that reinforces PDH inhibition and stimulates PC). This acetyl-CoA can then be used to synthesize fats in the cytosol, a process that's started by acetyl-CoA carboxylase (ACC)--another biotin-dependent enzyme.
Roles of pyruvate carboxylase in human diseases: from diabetes to cancers and infection
Yes, PC-derived oxaloacetate can refill the TCA cycle, but so does ketoglutarate from glutamate or glutamine, and they can cooperate.
Two other biotin-dependent enzymes (MCC and PCC) are involved in amino acid metabolism and can also channel the products to refill the cycle. These products would enter the TCA cycle right where ATP is synthesized through substrate-level phosphorylation (Tommy), with higher chances of bypassing inhibitions.
Therefore, all 4 biotin enzymes can converge in anabolic processes that may be problematic in the context of cancer.
To compound the concerns, simple conversion of pyruvate to oxaloacetate is one step away from aspartate synthesis, needed for the upregulated nucleotide synthesis.
This aspartate can also participate in the malate-aspartate shuttle, that serves to import cytosolic NADH. Normally, oxalate is formed from malate, but if this is reversed with the help of pyruvate carboxylase, the shuttle could perhaps work in reverse, and it would contribute to the export of NADH, with higher cytosolic NADH/NAD⁺ promoting lactate synthesis. In addition, it can be an alternative way to regenerate NAD⁺ when respiratory complexes are compromised, to allow the TCA cycle to keep functioning.
In fairness, some of these processes concentrate in liver and kidneys, and biotin may also relieve the burden in supporting clearance of excess lactate from cancerous tissues (lactate → pyruvate –B7→ oxaloacetate → pyruvate enolphosphate →→ glucose), possibly more so than thiamin, as local pyruvate oxidation without redistribution as glucose could perhaps overwhelm such organs. However, thiamin could be of better service for other tissues, that clear lactate through complete oxidation.
Even in cases where biotin supplementation normalizes glucose metabolism, the anabolic component can't be discarded.
Some Aspects of Carbohydrates Metabolism in Biotin-Deficient Rats
"It is possible, therefore, that these changes in the fatty acid composition of the lipid might alter the structural integrity of mitochondria with the consequent effect on oxidative phosphorylation. This defect, as reflected by amino acid incorporation studies, was compensated during early stages of the deficiency when the animals received an oxidizable substrate such as succinate (see reference 1) or fructose or sorbitol in the basal diet. It is, therefore, possible that a moderate decrease in oxidative phosphorylation does not limit the efficiency of the biotin-deficient animal as long as adequate levels of oxidizable substrates are maintained. However, in advanced deficiency as observed after 8 weeks on the deficient diet, succinate, sorbitol, or fructose feeding did not help the animal. Only administration of biotin restwed fatty acid synthesis and the integrity of mitochondria for normal oxidative phosphorylation."
It's no wonder that symptoms of biotin deficiency point to anabolic defects, such as disturbed skin lipids.
I would be careful with its supplementation in advanced cancer and observe reactions. It's preferable to avoid B-vitamins formulas and have the vitamins separately for better control.
This is not to suggest that thiamin, niacin, and aspirin are entirely beneficial in cancer because they're not, but their positive outweigh negative effects. Biotin isn't invariably problematic, but seems riskier.
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@max anything to update on this? also https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051000/ https://bioenergetic.forum/post/22196
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To reinforce, the bright side of biotin is unlikely to be in diverting pyruvate away from lactate when its oxidation is inhibited, but in helping to process this lactate once it's taken up by normal cells.
For an idea of the extent of lactate production:
Lactate Metabolism in Patients with Metastatic Colorectal Cancer
"Using an isotope tracer technique, we found increased rates of lactate production in 20 patients with metastatic colorectal cancer [Ca] compared to 13 control subjects [C] of comparable age and sex (15.6 ± 1.3 μmol/kg/min versus 10.4 ± 0.6 μmol/kg/min; p < 0.01)."
Their most extreme case produced lactate at 34.5 μmol/kg/min (3.48 mol/70 kg/24 h).
2 lactates per 1 glucose:
- 3.48 ÷ 2 → 1.74 mol/70 kg/24 h
Unit conversion:
- 1.74
mol/70 kg/24 h × 180 g/mol= 313 g/70 kg/24 h
They discount the typical production based on the control group, which was 10.4 μmol/kg/min (1.05 mol/70 kg/24 h):
- 1.05 ÷ 2 → 0.53 mol/70 kg/24 h
Unit conversion again:
- 0.53
mol/70 kg/24 h × 180 g/mol= 95 g/70 kg/24 h
The difference:
- 313 – 95 = 218 g lactate/70 kg/24 h
However, lactate must not be a burden to normal tissues if it's widely distributed and metabolized oxidatively, because it's the catabolism of glucose continued elsewhere (glucose →→ pyruvate
→ lactate → pyruvate→→ carbon dioxide + water)."When control subjects were compared to the cancer patients, no significant difference was observed in the percentage of CO2 derived from lactate oxidation (21 ± 1.6 versus 25.3 ± 1.7%)."
"The percentage of the lactate production which was immediately oxidized was not related to the rate of lactate production, the mean values in the control subjects and cancer patients being 68.3 ± 2.7 and 62.1 ± 2.4%, respectively.
"Lactate disposal by mechanisms other than immediate oxidation, i.e., the difference between the lactate production rate and the oxidation rate, was significantly increased (p < 0.001) in the cancer patients (227 ± 24 versus 128 ± 8 μmol/sq m/min or 6.0 ± 0.7 versus 3.2 ± 0.3 μmol/kg/min)."
"The rate of nonoxidative lactate disposal was directly related to the lactate production rate (Chart 4). At least in part, conversion of lactate to glucose may account for the greater difference observed in the nonoxidative disposal in cancer patients in whom the percentage of glucose derived from lactate was significantly increased, (23.1 versus 15.8 ± 1.7%; p < 0.01). The percentage of glucose derived from lactate was also directly related to the lactate production rate (Chart 5)."
The burden comes when lactate reforms glucose, which occurs concentrated in specific organs. Not only the synthesis of glucose from lactate consumes more energy (–6ATP) than is produced (+2ATP) in the partial breakdown of glucose, but the energy produced may be left behind where breakdown occurred, making the site of clearance an exclusive energy consumer. Yet, the body has the option to oxidize it at any time in place of glucose to avoid ATP shortage.
But an additional concern is that glycogen is found in cancer cells as well, giving them metabolic independence to maintain activity when nutrients are scarce.
Cells go through cycles of depletion and repletion, and with excess lactate around, it's possible that part of it is channeled to glycogen synthesis. Therefore, we have to wonder where glucose resynthesis (through pyruvate carboxylase) is desirable.
An assumption is that tumor lactate stems only from cancer cells, but it can be formed in surrounding cells (fibroblasts or macrophages, for example) and cancer cells may exploit it to their advantage, whether in oxidizing it or as speculated above. It's also possible to have neighboring cancer cells fermenting and respiring in cooperation.
This adds a layer of complication in trying to explain the benefit of nutrient supplementation with a focus on local metabolism.
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Glycolysis can be reversed starting from different molecules, and PC-derived oxaloacetate is one of the ways. Reverse glycolysis doesn't have to end on glucose (or glycogen) either, reversal can be partial to get to the branching points, as an alternative means to yield products needed for biosynthesis.
The issue relates to the carefree thiamin supplementation. Enthusiasts treat it as if it could only serve to disinhibit pyruvate dehydrogenase as intended, but it's not the case.
B Vitamins and Their Role in Immune Regulation and Cancer
TKT and KGDH can be overactive, whereas PDH underactive in cancer. Additional thiamin would be in favor of the ongoing activity of TKT and KGDH, while going against the inhibition of PDH.
- Role of Thiamin (Vitamin B-1) and Transketolase in Tumor Cell Proliferation
- Thiamine supplementation to cancer patients: A double edged sword
For thiamin to get to mitochondria, it must first pass through the cytosol, where it's activated to thiamin diphosphate. Depending on the exact site of activation, TKT is cytosolic and may have privileged access to extra thiamin.
Linking vitamin B1 with cancer cell metabolism
If thiamin reaches mitochondria in therapeutic amounts, PDH must compete with KGDH for it, and PDH is more susceptible to regulation and inhibition than KGDH. Even with proper amounts of active thiamin, PDH may remain inhibited as a consequence of other controlling factors. And the TCA cycle (with KDGH) can be running independently of PDH. For example, with acetyl groups from fatty acids and ketoglutarate from glutamate.
Consider this:
"The thiamine concentration in plasma is observed to be in the range of 10-20nM. We used 10nM thiamine concentration as a control group to simulate the physiological levels of thiamine observed in human plasma."
Below is a projection relying on maximum plasma concentrations after each oral dose (thiamin HCl).
Pharmacokinetics of high-dose oral thiamine hydrochloride in healthy subjects
It's an optimistic curve. Suppose that rate keeps increasing and we reach a maximum concentration of 1200 nmol/L (0.0012 mmol/L or mM) with 3 g of oral thiamin (although the dose can get much higher without risk of toxicity). If you think that 3000 nM was an exaggerated level, the following experiment with cultured cells is often mentioned to defend supplementation:
High Dose Vitamin B1 Reduces Proliferation in Cancer Cell Lines Analogous to Dichloroacetate
At about 2 mM (2,000,000 nM) of the tested concentrations is where they started to observe a decrease in proliferation. The half-inhibition concentrations were 4.9 and 5.4 mM.
Yet, we have this experiment that's more encouraging:
The effect of thiamine supplementation on tumour proliferation: a metabolic control analysis study
The highest dose led to a 10% reduction in proliferation. The extrapolated dose may be something like 250 mg/person, but administration was subcutaneous.
⠀(from here)In any case, for the overflow of thiamin to target PDH and make the effect prevail, the dose has to be extreme.
Considering the multiple influences on PDH, it remains possible that a major benefit of thiamin comes instead from its impact on carbonic anhydrases. Ray pointed out that it can work as an inhibitor and Jorge posted this experiment on the Antitoxin Forum:
- Compound 3: thiamin
It's feasible:
Fingers crossed that it applies to other carbonic anhydrase forms as well.
The Expression of Carbonic Anhydrases II, IX and XII in Brain Tumors
Despite carbonic anhydrases 9 and 12 being exposed on the surface of cells, the cells might be clustered in poorly vascularized tissues. If it's not a blood cancer, we can expect a sharp decrease in the thiamin concentration as we get to the core of this mass, which strengthens the idea that it's worth being extreme in supplementing it in cancer.
