Flavonoids are compounds that are naturally present in fruit and vegetables. Scientists have known for 20 years that they can help prevent colorectal cancer but have not fully understood the underlying biology.
Now, a new study describes a molecular mechanism through which a product of flavonoid digestion can inhibit cancer cell growth under certain conditions.
The study is the work of a team at South Dakota State University in Brookings, who report their findings in a recent issue of the journal Cancers.
In that earlier work, they saw how a salicylic acid derivative called 2,4,6-trihydroxybenzoic acid (2,4,6-THBA) was able to slow cancer cell growth.
They decided to search for natural sources of 2,4,6-THBA and found that it was also a compound that results from the digestion of flavonoids.
Metabolite of flavonoid digestion
Flavonoids begin to break down once they enter the intestines. Gut bacteria reduce them further into metabolites when they enter the colon.
Having observed these processes, scientists have proposed that the anticancer effects of flavonoids are due to their metabolites. One of these metabolites is the molecule 2,4,6-THBA.
“We hypothesized,” says senior study author Jayarama Gunaje, Ph.D., “that flavonoids decrease colorectal cancer due to the action of the degraded, or broken down, products rather than the parent compounds.”
“These areas are underexplored,” adds Gunaje, who is an associate professor in the College of Pharmacy & Allied Health Professions at the university. The study paper gives his name as G. Jayarama Bhat.
Testing 2,4,6-THBA on colon cancer cells
The new study is the first to investigate how 2,4,6-THBA, as a product of flavonoid breakdown in the gut, can help to prevent cancer of the colon or rectum.
The colon and rectum form part of the large intestine. With help from a range of gut bacteria, the final stage of digestion takes place in the colon, which then passes the remaining waste to the rectum to await evacuation through the anus.
According to 2016 statistics from the Centers for Disease Control and Prevention (CDC), colorectal cancers are the fourth most common type of cancer in the United States and also the country’s fourth most common cause of cancer deaths.
During 2016, the latest year for which figures are available for the U.S., some 141,270 people found out that they had cancer of the colon or rectum, and 52,286 died from these types of cancer.
In the new study, the researchers found that 2,4,6-THBA can bind to three enzymes that typically help cells to divide. They wondered if this ability was sufficient to block cancer.
However, when they tested the effect of 2,4,6-THBA on colon cancer cells, they found that there was none.
The metabolite needs a transporter
A search of previous studies on 2,4,6-THBA revealed that the metabolite could not enter cells without the aid of a transporter protein called SLC5A8.
Gunaje points out, however, that cancer cells can disable the transporter protein with a genetic mutation. This has a protective effect that allows the cancer cells to proliferate.
Further tests, including some with cancer cells that express SLC5A8, demonstrated that 2,4,6-THBA was able to enter cells that expressed the transporter protein but could not gain access to cells that did not.
The researchers say that these results show that 2,4,6-THBA needs the transporter to inhibit cancer growth.
Gunaje explains that the flavonoid metabolite likely has two ways of helping to prevent cancer. The first way is that by slowing the rate of cell division, 2,4,6-THBA gives immune cells a chance to locate and destroy the cancer cells.
The second way that 2,4,6-THBA likely helps to prevent cancer is that by slowing cell division, it gives the cell more time to repair any damage to its DNA.
Damage to DNA is how mutations occur, which raises the risk of cells growing out of control and starting tumors.
The researchers are already investigating which gut bacteria produce metabolites from flavonoids. They foresee the possibility of developing probiotics that could help to prevent colorectal cancer.
“We have so many drugs to treat cancer, but almost none to prevent it. Therefore, demonstrating 2,4,6-THBA as a protective agent against colorectal cancer has immense potential health benefits.”
Jayarama Gunaje, Ph.D.