Derivative of vitamin B3 prevents liver cancer in mice

Researchers from the Spanish National Cancer Research Centre (CNIO), have produced the first mouse model that faithfully 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 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.

A MOUSE MODEL FOR HUMAN HEPATIC CANCER

One obstacle to the study of human HCC is the absence of mouse models that replicate the disease, which could be used to investigate molecular pathways or new therapies. 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 and Head of the Growth Factors, Nutrients and Cancer Group in the BBVA Foundation-CNIO Cancer Cell Biology Programme. “It is still not totally clear, however, why the deficit in NAD+ causes these lesions,” he adds.

ENERGY METABOLISM AND CANCER

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+,