Novel Vitamin Discovered Offers Clues for Cancer Chemotherapy

In a fusion of biochemistry and genetics, Dartmouth Medical School cancer researchers have discovered a new vitamin in a molecular pathway central to such processes as gene regulation, metabolism and aging.And, they found, milk contains this nutrient. Their study defines another metabolic route to a compound called NAD (nicotinamide adenine dinucleotide) one of the cell's essential small molecules, and suggests that therapeutic approaches for cancer or heart disease may depend on the enzyme pathways identified.The research was published in the May 14 issue of Cell by Drs. Charles Brenner, associate professor of genetics and of biochemistry, and Pawel Bieganowski, a postdoctoral fellow. NAD, vital for all organisms, from bacteria to humans, is versatile, working both as a partner that helps enzymes and as an ingredient that other enzymes consume.

Niacin, or vitamin B3, a mixture of the NAD precursors nicotinic acid and nicotinamide, prevents pellagra and can help control cholesterol. Anti-cancer drugs including tiazofurin and benzamide riboside are converted to toxic NAD analogs; proteins dependent on NAD prolong lifespan in experimental systems.

Enzyme studies in Brenner's laboratory at the Norris Cotton Cancer Center revealed a novel twist.Yeast cells where every known NAD biosynthetic pathway was shut down, did not die, yet no vitamins or supplements were known to keep the cells alive.The researchers discovered that an NAD precursor, nicotinamide riboside (NR), known as a vitamin only in certain bacteria, also served as a vitamin in yeast and could prevent death. Using what Brenner termed a "biochemical genomics approach," they zeroed in on the gene for a novel kinase enzyme in yeast and humans responsible for this vitamin conversion pathway.Then they found the vitamin in milk.

Their findings upend some decades-old assumptions underlying biosynthetic schemes for NAD and refocus the pharmacology of cancer drugs that look like nicotinamide riboside. As a nutrient, NR may be an alternative to niacin, which helps lower cholesterol but has uncomfortable flushing effects.And, while tiazofurinrelated drugs have potential against cancer, they are unpredictable so kinase screening may benefit patients."Certain tumors respond, while others don't, so if we can select the right patients we will have a more effective treatment strategy," Brenner said."In the future, testing for nicotinamide riboside kinase expression might be used to identify the patients that are likely to respond to this class of drugs."

Back to May/June 2004 DMS Digest