Over the last 5-6 years, a number of high profile articles (many of them, including the new one below, published in the top journal Nature) confirmed lactate as not only an “oncometabolite”, but as a direct driver of cancer growth, aggressiveness, metastases, and ultimately death of the patient. Lactic acidosis type B, which is often seen in patients with advanced cancer, has about 40% lethality even if the patient is in the hospital and receiving the most advanced treatments available for metabolic acidosis. So, nothing benign or insignificant about lactate, as medicine would have us believe. The new study below now demonstrates that lactate has another “trick” up its sleeve – i.e. increasing resistance of the “cancer” cells to chemotherapy. I shudder at the thought of how many cancer (and other) patients deteriorate (or even die) iatrogenically due to the administration of the so-called “Ringer Lactate” solution – a common “hydration” therapy given by IV in hospitals to critically ill patients, including cancer patients. But I digress.
Interestingly, lactate achieves this enhanced resistance to chemotherapy by increasing the activity of enzymes involved in DNA repair inside “cancer” cells. Since such cells are known to have a high rate of DNA damage/mutation, it makes sense that “cancer” cells have increased DNA repair processes. However, most of the DNA repair processes consume a lot of NAD+, especially the PARP-1 and CD38 enzymes, which further lowers the critically-important mitochondrial NAD+/NADH ratio in the already highly reductive “cancer” cells. Conversely, PARP-1 and CD38 inhibitors have been shown to be therapeutic for cancer, which is undoubtedly due to the ability of such inhibitors to “spare” the NAD+ the sick organism so desperately needs. Thus, the main mechanism of lactate’s pro-cancer effects may very well turn out to be its NAD+ depletion by activating DNA repair in “cancer” cells. To make matters worse, lactate is itself a reductant and consumes NAD+ directly when it is oxidized back to pyruvate by the enzyme lactate dehydrogenase (LDH). Interestingly, the study found that inhibition of lactate generation by the administration of an LDH inhibitor was therapeutic and cancelled the resistance of “cancer” cells to chemotherapy. Now, if only there was a way to attack all of those pathways simultaneously with a simple, cheap and safe molecule…Luckily, niacinamide is just such a substance. Not only is niacinamide the main endogenous precursor to NAD+, but it is also a powerful inhibitor of the NAD+ consuming enzymes PARP-1 and CD38. Thus, niacinamide raises NAD+ by being both a precursor and inhibitor of NAD+ consumption. In corroboration, niacinamide has been shown to reliably lower lactate in humans. Other powerful lactate generation inhibitors include vitamin B1 (thiamine) and vitamin B7 (biotin). Coincidentally, the combination of those vitamins, together with aspirin, was able to induce complete regression in my recent xenograft study with the human jeko-1 (mantle cell lymphoma) cell line. Thus, we can conclude once again that “cancer” is metabolic in origin and likely just a symptom of a highly reduced (both literally and figuratively) metabolic state, and administering substances that shift the metabolic state towards oxidation may very well cure the “cancer”. Oh, and last but not least, the study discloses (perhaps inadvertently) that LDH inhibitors are used clinically for the treatment of epilepsy – a condition medicine considers both mysterious in origin and incurable. Thus, I think we can safely conclude that epilepsy, just like cancer, is also nothing but a symptom of severe (brain) energetic depletion, and also amenable to simple treatment as described above:-)
https://www.nature.com/articles/d41586-024-02731-9
“…The molecule lactate is a waste product of the metabolism of sugar without oxygen — a metabolic pathway preferentially used by cancer cells to generate their energy. Metabolomics analysis reveals that lactate in tumour cells promotes resistance to chemotherapy, and sheds light on the molecular mechanism that underlies this unexpected role of lactate in cancer.”
https://www.nature.com/articles/s41586-024-07620-9
“…The Warburg effect is a hallmark of cancer that refers to the preference of cancer cells to metabolize glucose anaerobically rather than aerobically1,2. This results in substantial accumulation of lacate, the end product of anaerobic glycolysis, in cancer cells3. However, how cancer metabolism affects chemotherapy response and DNA repair in general remains incompletely understood. Here we report that lactate-driven lactylation of NBS1 promotes homologous recombination (HR)-mediated DNA repair. Lactylation of NBS1 at lysine 388 (K388) is essential for MRE11–RAD50–NBS1 (MRN) complex formation and the accumulation of HR repair proteins at the sites of DNA double-strand breaks. Furthermore, we identify TIP60 as the NBS1 lysine lactyltransferase and the ‘writer’ of NBS1 K388 lactylation, and HDAC3 as the NBS1 de-lactylase. High levels of NBS1 K388 lactylation predict poor patient outcome of neoadjuvant chemotherapy, and lactate reduction using either genetic depletion of lactate dehydrogenase A (LDHA) or stiripentol, a lactate dehydrogenase A inhibitor used clinically for anti-epileptic treatment, inhibited NBS1 K388 lactylation, decreased DNA repair efficacy and overcame resistance to chemotherapy. In summary, our work identifies NBS1 lactylation as a critical mechanism for genome stability that contributes to chemotherapy resistance and identifies inhibition of lactate production as a promising therapeutic cancer strategy.”
