First some prose and background from my understanding of cancer metabolism- and then a look at a new study on targeting reductive stress in cancer. Lastly, a small look into some probable methods of getting the cell out of the highly reduced state.

Now we know that the hibernating and diabetic cell seems to be in a redox state that is tilted more towards reduction in the balance of oxidised and reduced electron carriers. This reductive state, where the electrons are “stuck” before a bottleneck, where they cannot be delivered towards energy production, is known to cause problems in the cells – being hindered in the direction of oxidative phosphorylation, the electrons can go in the direction toward fatty acid synthesis and lactate production (among other pathways). The high uptake of glucose and anaerobic glycolysis has long been known to be a hallmark of cancer, (the warburg effect) where the cancer is in such a reductive state, as it has no NAD+ to deliver it’s electrons to.

(As a side note, fatty acid synthase/de novo lipogesis, is also highly upregulated in cancer cells. https://www.nature.com/articles/s41389-023-00460-8)

The glucose gets turned into lactate, and in turn regenerates NAD+. The highly acidic lactate gets shuttled out of the cell in an increased rate, making the extracellular microenvironment more acidic, and the intracellular environment more basic.

The inside of the cell, with a more basic environment, takes up more water, and it makes the cell grow in size proliferate .

The outside of the cell, with high levels of lactate, now uses the lactate as a signal of “hypoxia” – inducing growth factors that help the cancer cell to get new blood vessels to be produced (angiogenesis) -another hallmark of cancer.

The Cancer cell is a cell in such a mess, in a state of reductive stress, and constant excitation. It’s as if, all the sophisticated eukariotic programming has been turned off, and the cell devolves in to an earlier evolutionary state, going back to the early programming of prokaryotic cells. Dedifferentiation (turning of specialization) and growth with no direction or coordination. With Chromosomal chaos, it’s as if the cancer cell is a new species- no longer a part of i highly coordinated organism.

My thoughts and understanding aren’t so farfetched – it has been suggested that the Warburg effect is in itself the driver of dedifferentiation through “epigenetic programming”

“Therefore, the high production of lactate in tumor cells is likely not attributed to overexpression of LDH, but rather due an excess of NADH in the cells, which drives the conversion of pyruvate-to-lactate.”

…

“Excessive NADH not only converts pyruvate-to-lactate, but also converts α-KG to L-2-hydroxyglutarate (L-2-HG). Like D-2-HG produced by mutant isocitrate dehydrogenase (mIDH), L-2-HG inhibits various dioxygenases that use α-KG as a substrate¹⁹, including ten-eleven translocation (TET) DNA demethylases, Jumonji domain-containing histone demethylases (JMJDs), and prolyl hydroxylases (PHDs), leading to epigenetic dysregulation (DNA and histone hypermethylation), as well as upregulation of HIF, resulting in cell dedifferentiation¹⁶.”

…

“In addition, multiple metabolic stress conditions inhibit the glucose flux into mitochondria, resulting in lower intracellular acetyl-CoA generation from pyruvate^20,21. Acetyl-CoA, essential for histone acetylation and crucial for gene transcription and cell differentiation, becomes deficient under metabolic stress conditions. This deficiency inhibits histone acetylation, leading to suppressed tissue differentiation”

The Warburg effect drives dedifferentiation through epigenetic reprogramming

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10845936/

One could easily speculate:

Might reductive stress be a driver of cancer itself, making the highly coordinated genetic programming go haywire?

Targetting reductive stress

Now we shall see how one study dives into one of the metabolic changes that’s common in many cancers, and how targeting that pathway might be of great interest.

Nicotinamide N-methyltransferase (NNMT): A key enzyme in cancer metabolism and therapeutic target

https://www.sciencedirect.com/science/article/abs/pii/S1567576924017302

A newly published review looks closer on a key enzyme that has been upregulated in many cancers:

“The enzymatic function of NNMT is centered on the methylation of nicotinamide (NAM), utilizing S-adenosylmethionine (SAM) as the methyl donor, which results in the generation of S-adenosyl-L-homocysteine (SAH) and methyl nicotinamide (MNAM). This metabolic process reduces the availability of NAM, necessary for Nicotinamide adenine dinucleotide (NAD⁺) synthesis, and generates SAH, precursor to homocysteine (Hcy). These alterations are theorized to foster the resilience, expansion, and invasiveness of cancer cells. Furthermore, NNMT is implicated in enhancing cancer malignancy by affecting multiple signaling pathways, such as phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT), cancer-associated fibroblasts (CAFs) and 5-Methyladenosine (5-MA), epithelial-mesenchymal transition (EMT), and epigenetic mechanisms. Upregulation of NNMT metabolism plays a key role in the formation and maintenance of the tumour microenvironment.”

So the enzyme causes NAD+ depletion, and and upregulation in homocysteine, which is hypothesised to enhance the cancer growth, resilience and invasiveness.

The enzyme also seems to be related in the turning on or off certain signalling pathways that increase the malignancy of the cancer.

A very interesting section that seems to confirm that NAD+ depletion supports the warburg effect in the cancer cell:

“Cui et al. [40] demonstrated that the genetic ablation of NNMT in ESCC cells significantly increased their sensitivity to 5-fluorouracil (5-FU), largely by promoting apoptosis. This was accompanied by a decrease in the expression of enzymes related to glucose metabolism and glycolysis, leading to reduced lactate production and glucose uptake. The suppression of the Warburg effect further suggests that increased NNMT expression may enhance the survival of cancer cells in chemotherapy-rich…” environments? ( a word is missing in the publication)

So knocking out the gene for NNMT makes the cancer cell more prone to commit suicide/apoptosis, because it now has a lower capacity for lactate production. Very interesting to say the least!

Modern medicine, constantly being on the lookout for the next block buster drug has looked into interfering with NNMT production with a form of RNA therapy.

“Silencing NNMT through small interfering RNA (siRNA) has been shown to reduce cancer cell proliferation, migration, invasion, and resistance to treatment [51], [80]”

But i could think of other very cheap and easy ways to start.

To push the redox balance more towards oxidation, one could start by looking into methionine restriction, so that methyl donation is slowed.

One could also imagine other ways to increase the NAD+ pool, such as supplementing or increase the regeneration of NAD+ through uncoupling oxidative phosphorylation.

Seems the authors believe that homocysteine plays a role – which is why I could imagine the cysteine restriction might also be an idea to study further.

At least this interesting review looks into protein restriction and looks further into how restricting amino acids such as cysteine and methionine might have anti cancer effects

Dietary Manipulation of Amino Acids for Cancer Therapy. https://www.mdpi.com/2072-6643/15/13/2879

Seems cysteine helps the cancer to remove ROS and avoiding apoptosis:

“Mechanistically, Cys restriction may induce anticancer activity by reducing the capacity of cancer cells to eliminate ROS. Cancer cells produce high levels of ROS, which may accumulate and produce cell death [8]”

Methionine restriction can probably reduced methyl donor SAM

“Mechanistically, Met limitation restricts protein synthesis, cell division, and tumor growth. Met restriction can also reduce the cellular levels of the methyl donor SAM, which may alter the DNA methylation and epigenetics in dividing cancer cells. “

Now we saw in the first study that

“The enzymatic function of NNMT is centered on the methylation of nicotinamide (NAM), utilizing S-adenosylmethionine (SAM) as the methyl donor, which results in the generation of S-adenosyl-L-homocysteine (SAH) and methyl nicotinamide (MNAM).”

So – restricting methionine might have something to it!