Team discovers that Nicotinamide Riboside supplementation prevents liver cancer in mice

Liver cancer is one of the most frequent cancers in the world, and with the worst prognosis; according to the World Health Organisation (WHO), in 2012, 745,000 deaths were registered worldwide due to this cause, a figure only surpassed by lung cancer. The most aggressive and frequent form of liver cancer is hepato-cellular carcinoma (HCC); little is known about it and there are relatively few treatment options.

 Researchers from the Spanish National Cancer Research Centre (CNIO), have produced a mouse model that reproduces the steps of human HCC development, from the appearance of the first lesions in the liver to the development of metastasis. The results, published in the the journal Cancer Cell, indicate that diets rich in nicotinamide riboside, a derivative of vitamin B3, protect these mice from developing HCC in its most initial stage, when genotoxic stress is damaging cellular DNA. They also show a curative effect of the diet in those mice that had previously developed the disease.

Given that human HCC is associated to alterations in hepatocytes survival, and that the URI oncogene plays a role in this process, the researchers genetically engineered mice that contained high levels of URI only in the liver, in a controlled manner over time.

At 30 weeks, the mice with high levels of URI generated sporadic tumours in the liver and even metastasis when the induction lasted longer. The study details how deficiency in nicotinamide adenine dinucleotide (NAD+), a universal compound found in living organisms that is needed to burn calories via cell metabolism, orchestrates the development of the disease.

“An increase in URI reduces cellular NAD+ and as a consequence produces genotoxic stress and DNA damage”, says Nabil Djouder, leader of the study.  “It is still not totally clear, however, why the deficit in NAD+ causes these lesions,” he adds.

The appearance of DNA damage is the first link in the chain of events that activate the carcinogenic process in the liver, even before apoptosis or cell death, as has been described in the literature. “We normally say that oncogenes induce DNA damage. Now we may be able to say, more appropriately, that oncogenes induce NAD+ depletion [or deficits in NAD+] which causes DNA damage,” says Djouder.

The inverse relationship between NAD+ and cancer awakened the curiosity of the researchers: could an increase in NAD+ have beneficial effects on the disease? When the scientists supplemented the diet in genetically modified mice with nicotinamide riboside, a derivative of vitamin B3 that increases intracellular levels of NAD+, they did not observe tumour development. Surprisingly, when they gave this diet to mice that had already developed the disease, the size of the tumours was reduced and they eventually disappeared.

The results have been reproduced in other types of cancer such as pancreatic cancer. “We observed the same results in mice with pancreatic adenocarcinoma with regards to DNA damage, so we could conclude that this treatment is effective on tumours caused by oncogene-induced DNA damage and thus, deficit in NAD+,” says Krishna Tummala, first author of the study.

In addition to working with the mouse model, the authors have collated the results of nearly a hundred human samples. “Those from patients with HCC contain URI levels that double those of healthy samples,” according to the article. The data, which also associates URI with a worse prognosis or evolution of the illness, suggests that the gene could be a possible new HCC marker, and nicotinamide riboside boosting NAD+ levels may have a human relevance.

The dosing used was 500mg/Kg/day. Using FDA specified guidelines  we can calculate the Human Equivalent Dose (HED) for the NR diet given to the mice. Using this guideline 500mg/kg dosing in mice translates into a HED of approx. 41mg/kg. Or into approximately 2.8gram daily nicotinamide riboside dose for a person weighing 70kg. Typical supplements on the market have serving sizes of 250mg. It should be noted that this dose is over the limit wrt to side effects and safety and hence likely needs to be done under medical super vision.

You can find the relevant studies here & here  and a news article here.

 

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