Compound derived from plant components inhibits growth of intractable breast cancer: Discovery by Gifu University

A research group at Gifu University and other institutions has developed a compound that inhibits the growth of "triple-negative" breast cancer, a type particularly difficult to treat, using components from a plant called Carex kobomugi (Japanese sedge). The team plans to investigate the drug's effectiveness through future testing using mice.

C. kobomugi is known as a "rescue plant" because it was traditionally eaten during times of starvation. It grows naturally on coastal sand dunes. A research group including Associate Professor Satoshi Endo, who specializes in drug discovery science at the United Graduate School of Drug Discovery and Medical Information Science, Gifu University, has long been searching for substances that are effective against prostate cancer. The group previously identified a compound in C. kobomugi called "KC-A" that possesses inhibitory effects.

Prostate cancer grows through the action of androgens. While breast cancer primarily grows via female hormones (estrogens), androgens are also involved. Consequently, the research group expanded their study to include triple-negative breast cancer.

Triple-negative breast cancer is characterized by the absence of three proteins involved in cancer cell growth. Among various types of breast cancer, cells of this type grow rapidly. It is often fatal by the time it is discovered. There are few molecular-targeted drugs, and even anti-cancer drugs that have been developed in recent years have been deemed "ineffective" in the clinical trial stage, making development difficult. On the other hand, with the development of genome therapy, the mechanism of what genes cause cancer to increase is becoming clearer.

In triple-negative breast cancer, excessive androgens are produced and bind to receptors, triggering cell proliferation. KC-A reduces the production of this androgen and the number of receptors, but it is derived from natural plant sources and has limited effectiveness. Therefore, the shape of the compound was modified using computational methods to make it easier to bind to the enzyme that synthesizes androgens. This was named WH23.

When WH23 was applied to human-derived cells with triple-negative breast cancer in the laboratory, it was found to be effective even at low concentrations. In addition, while only a few dozen milligrams of naturally occurring KC-A can be obtained from one kilogram of C. kobomugi, it is now possible to synthesize KC-A and WH23 in gram-scale quantities required for animal experiments.

To determine the mechanism by which they worked, KC-A and WH23 were then tested on human triple-negative breast cancer cells. As a result, in addition to cutting off the pathway supplying androgens to cancer cells, it also worked to prevent the androgen receptors themselves from being generated. These two effects suppressed the growth of cancer cells.

Based on these results, Endo intends to proceed with experiments on mice. He commented: "In mouse trials, administration will likely be via intraperitoneal or intravenous injection. However, for human use, an oral medication would be ideal to reduce the burden on patients. While we focused on cancer this time, androgen action also causes symptoms like hair loss. Since C. kobomugi extract contains many compounds similar to KC-A, we are also considering whether the extract could be used in supplements."

This research was supported by the Japan Agency for Medical Research and Development (AMED), the Suzuken Memorial Foundation, and the Shorai Foundation for Science and Technology. The findings were published in the Dutch scientific journal European Journal of Medicinal Chemistry on February 6 and announced by Gifu University on February 13.