“Non-drug” cancer proteins become drug-resistant due to the shrub

A chemist at Purdue University has found a way to synthesize a compound to fight a “non-drug” cancer protein, with benefits in a variety of cancers.

Inspired by a rare compound found in a North American shrub, Mingji Dai, a professor of chemistry and scientist at the Purdue University Center for Cancer Research, studied the compound and found a cost-effective and effective way to synthesize it in the laboratory. . The compound – curcone D – has the potential to help fight a protein found in many cancers, including some cancers of the breast, brain, colorectal, prostate, lung and liver, among others. The protein, nicknamed BRAT1, had previously been considered “non-drug” for its chemical properties. In collaboration with Alexander Adibekian’s group at the Scripps Research Institute, they linked curcone D to BRAT1 and validated curcone D as the first BRAT1 inhibitor.

Curcones are compounds that come from a shrub called Jatropha curcas, also called the purge nut. Originally from America, it has spread to other continents, including Africa and Asia. The plant has long been used for medicinal properties – including cancer treatment – as well as being a cheap source of biodiesel.

Dai was interested in this family of compounds – curcones A, B, C and D.

“We were very interested in the new structure of these compounds,” Dai said. “We were intrigued by their biological function; they showed quite strong anti-cancer activity and can lead to new mechanisms to fight cancer.”

The researchers tested the compounds on breast cancer cells and found that curcuzone D is extremely effective in shutting down cancer cells. The protein they were targeting, BRAT1, regulates the response to DNA damage and DNA repair in cancer cells. Cancer cells grow very fast and produce a lot of DNA. If scientists can damage the DNA of cancer cells and prevent them from repairing it, they can stop the growth of cancer cells.

“Our compound can not only kill these cancer cells, it can stop their migration,” Dai said. “If we can prevent cancer from metastasizing, the patient can live longer.”

Stopping the spread of cancer throughout the body – metastasis – is the key to preserving the life of a cancer patient. Once the cancer begins to migrate from its original organ into various body systems, new symptoms begin to develop, often threatening the patient’s life.

“To kill cancer cells and stop migration, there are other compounds that do that,” Dai said. But when it comes to inhibiting the BRAT1 protein, there are no other compounds that can do that.

Dai and his team believe that, as effective as curcone D is, it can be even stronger as part of a combination therapy. They tested it with a DNA-damaging agent, which has already been approved by the Food and Drug Administration, and found that this combination therapy is much more effective.

One difficulty in studying curcumin as potential treatments for cancer is that while the shrub they come from is common and inexpensive, it takes massive amounts of shrub to produce even a small amount of compounds. Even then, it is difficult to separate the compounds they were interested in from the rest of the chemicals in the bush roots.

“In nature, the plant does not produce much of this compound,” Dai said. “You would need up to 100 kilograms of dried roots of the plant to get only about a quarter teaspoon of the substance – a yield of 0.002%.”

That low yield is relevant to production, because if it is effective as a treatment for cancer, pharmacists will need much more. In addition, having an abundant amount of compounds makes their study easier, faster and less expensive.

“That’s why a new synthesis is so important,” Dai said. “We can use the synthesis to produce more compounds in a purer form for biological study, allowing us to advance the field. From there, we can make analogues of the compound to improve its potency and reduce the potential for side effects.”

The next step will be to test the compound to make sure it is not toxic to humans, which researchers are optimistic about because the shrub it comes from has been used as a traditional medicine in many crops. Already, researchers from other entities have gone to great lengths to test the compound on the cancers they are studying, bringing hope for renewed therapies to treat the disease.

“Many of the most successful cancer drugs have come from nature,” Dai said. “A lot of low-hanging fruits, compounds that are easy to isolate or synthesize, have already been examined and taken over. We look for things that no one has thought of before. Once we have chemistry, we can build molecules that interest us and study their biological function. . ”