Study Reveals NR Slows Liver Cancer Progression in Mice

Nicotinamide riboside (NR) could slow the spread of cancer in mice with tumors and help them keep their weight up in the late stages of the disease.

Key Points:

Replenishing NAD+ with nicotinamide riboside (NR) could inhibit liver tumor growth and cancer metastasis.
NR could promote the overall health status of mice bearing tumors and with metastasis.
Boosting NAD+ by NR and NMN supplementation could be a novel strategy for the prevention of liver cancer progression.

Researchers from Sun Yat-sen University in Guangzhou, China, published results showing that taking NAD+ precursors stopped liver cancer from causing weight loss and metastasis. Liver cancer is the sixth most common cancer in the world and was the third leading cause of cancer-related deaths worldwide in 2020. In different mouse models of hepatocellular carcinoma (liver cancer), research published in Nutrients showed that increasing NAD+ levels by giving nicotinamide riboside may be an effective way to stop the progression of hepatocellular carcinoma.

The Trouble With Liver Cancer Treatment

The most common type of liver cancer is hepatocellular carcinoma, which accounts for about 90% of the cases. Even though there are different ways to treat hepatocellular carcinoma, the overall prognosis is often not good. This is because metastasis often develops and comes back. This is when cancer cells break away from where they started (primary cancer), travel through the blood or lymph system, and form new tumors (metastatic tumors) in other parts of the body.

Both “burning” or “freezing” the tumor (local ablation) and removing the tumor (resection) are options for treating early-stage hepatocellular carcinoma tumors. Using these techniques, over 70% of people with these initial tumors will still be alive after 5 years. But in advanced-stage cases with metastases that cause symptoms, the average time to live is only 1 to 1.5 years.

Early-stage hepatocellular carcinoma tumors can be treated with hepatic resection. But the recurrence of hepatocellular carcinoma is still a big worry because micro-metastases can form after resection, and new tumors can grow in an environment that is very cancer-causing. Post-hepatic resection, a five-year recurrence rate has been reported to be as high as 70%. So, we need to find new ways to stop hepatocellular carcinoma from getting worse as soon as possible.

Targeting NAD+ to Nix Liver Cancer

Several studies have shown that the metabolism of NAD+ could be a good place to start treating cancer. But it’s not clear what role NAD+ plays in the complicated process of how tumors grow and spread, and it’s still not clear whether adding more NAD+ can slow or speed up the growth and spread of hepatocellular carcinoma. Some studies have shown that when NAD+ levels are low, hepatocellular carcinoma cells in lab cultures can’t move or invade. However, other studies have shown that NAD+ depletion actually promotes tumor growth, spread, and metastasis. Also, it has been shown that increasing NAD+ with NAD+ precursors slows the growth and spread of tumors in both lab-grown cells and living animals.

Nicotinamide riboside (NR), a powerful NAD+ precursor that is found naturally in milk and is already sold as a nutraceutical, has been shown to raise NAD+ levels in both human blood and mouse liver by a large amount. Studies have also shown that taking NR supplements can lessen the damage that alcohol does to the liver, prevent liver scarring (called “fibrosis”), and help the liver heal. But only a few studies have looked into how NR might help prevent or treat cancer, and none have looked into how it affects cancer spreading.

NR Suppresses Liver Cancer Progression

With support from Lili Yang’s lab, Nengzhi Pang and Qianrong Hu did research at Sun Yat-sen University in Guangzhou, China. They looked at NAD+ levels in human liver samples. The Chinese research team found that the NAD+ levels in hepatocellular carcinoma tissues were significantly lower than those in normal liver tissues.

Yang and colleagues looked at the role of restoring NAD+ levels in the progression of hepatocellular carcinoma in mice. Many types of cancer cause weight loss, and the researchers found that mice injected with cancerous liver cells under the skin to form tumors and given NR lost less weight than mice not given NR orally (400 mg/kg/day). At the end of the intervention, the NR-treated mice had an 11.8% decrease in body weight, which was considerably lower than the 18.61% decrease in the control mice. In addition, there was no difference in daily food intake among groups of mice during the intervention period, indicating that NR did not affect the appetite of the mice. While NR doubled the NAD+ levels in these tumors made by injecting mice with liver cancer cells, the researchers didn’t find differences in either the tumor volume or the tumor index between the control and NR groups.

**(Pang et al., 2023 | *Nutrients*)** **Nicotinamide riboside supplementation alleviated malignancy-induced weight loss in mice.** (Left) Changes in weight loss in the mice during the intervention (right) Differences in weight loss among two groups after 40 days of intervention with NR (nicotinamide riboside) Red dots represent control mice, and blue dots represent NR-treated mice.

Since cancer metastasis is a big part of how hepatocellular carcinoma gets worse and makes people sicker and causes them to lose weight quickly, the researchers changed their focus to see if NR supplements stopped cancer metastasis. To do so, they injected liver cancer cells into the bloodstream, which formed tumors in the liver and several other tissues, including the lungs.

The incidence rate of tumor metastasis was significantly lower in the NR (28.6%, 2/7), compared to the control group (100%, 6/6). After 32 days of treatment with NR, the bioluminescence signals showed that the number of tumors in the NR-treated mice was much lower than in the control mice. They found that NR treatment made a big difference in how many and how big the lung metastasis nodules were in mice compared to mice that didn’t get treated. They found that NR treatment made a big difference in how many and how big the lung metastasis nodules were in mice compared to mice that didn’t get treated. They also found that the number of hepatocellular carcinoma cells that spread to the head, bones, and abdomen was lower in the NR group than in the control group. This suggests that NR can reduce the number of hepatocellular carcinoma cells that spread to multiple organs.

**(Pang et al., 2023 | *Nutrients*)** **Liver cancer cells didn’t spread to other organs in mice when they were given NR.** After 37 days of NR supplementation, hepatocellular carcinoma cells spread to other parts of the mice’s bodies using a noninvasive imaging method. The coloring reflects the presence of cancer cells.

Can NAD+ Precursors Improve Liver Cancer Outcomes?

This research complements a study from 2014, in which researchers made a mouse with a mutation that blocked the pathway for making NAD+ from tryptophan, a different pathway than the one that uses NR and NMN. These mice had problems with DNA repair and liver tumor growth. When the researchers gave these mice food supplemented with NR (500 mg/kg/day) for the rest of their life upon reaching 3 weeks of age, their NAD+ pools increased roughly four times, the DNA damage response was fixed, and tumor formation stopped. The 2023 study adds to the evidence that increasing the amount of NAD+ might help fight cancer.

Researchers have been looking into the use of NAD+ precursors as a way to treat cancer. In addition to the research here on liver cancer, adding NAD+ precursors (niacin or nicotinamide) stopped breast cancer from spreading to the lung and other organs. Therefore, halting the loss of NAD+ that comes with aging can hinder the first step of tumor growth, which is the reprogramming of a tumor’s metabolism.