Cancer versus pepper?

A team at UT Southwestern Medical Center highlights how the long pepper contains a chemical shown to be effective against multiple cancer types

Kelsey Kaustinen
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DALLAS—Even as the science of medicine continues to advance, it doesn't stop researchers from looking back, as it were, to the lessons taught by natural medicine. The use of natural products offers a variety of benefits, one of the most prominent being that these compounds tend to be naturally optimized without any need for additional work.
One natural product being looked at now is pepper—specifically, a spicy Indian pepper plant called the long pepper that is found in southern India and southeast Asia. This plant dates back thousands of years and is tied to Ayurveda, one of the planet's oldest medical systems; in fact, it was once referred to by Hippocrates, who is known as the father of medicine. Long pepper is used as a homeopathic treatment for a variety of ailments, from heartburn, indigestion and cholera, to asthma, insomnia, epilepsy and psoriasis, as noted by WebMD. One chemical of interest in this plant is piperine, which is what makes long pepper (and black pepper) so pungent. Piperine is also thought to help fight parasites and to alter the lining of the intestines so that the body can better absorb some drugs.
The chemical responsible for long pepper's efficacy against cancer is Piperlongumine (PL), which has demonstrated activity against a variety of cancers, including breast, lung, prostate, colon, leukemia, lymphoma, gastric cancer and primary brain tumors.
A team at UT Southwestern Medical Center used X-ray crystallography to get a closer look at PL, creating molecular structures to examine how it changes once it's been ingested. After intake, PL converts to hPL, an active drug that silences the gene GSTP1, which produces a detoxification enzyme that is overabundant in tumors.
“Other labs have found that piperlongumine works through a protein called GSTP1, which is involved in detoxifying cells, and so we're interested in how piperlongumine interacts with GSTP1,” Dr. Kenneth Westover, assistant professor of biochemistry and radiation oncology and a member of the Harold C. Simmons Comprehensive Cancer Center, commented in a video regarding the work. “Our model for how piperlongumine may work is that it has to be intact to enter cells. It then is broken down once it enters the cell and can then interact with GSTP1, leading to cell death, which is useful for cancer therapy.”
“We are hopeful that our structure will enable additional drug development efforts to improve the potency of PL for use in a wide range of cancer therapies. This research is a spectacular demonstration of the power of X-ray crystallography,” he added.
Westover and the other authors of this study commented in the abstract that "Although hPL inhibits GSTP1 enzymatic activity in vitro, treatment of cells susceptible to PL with hPL did not have significant anti-proliferative effects, suggesting hPL is not membrane permeable. Altogether, our data suggest a model wherein PL is a prodrug whose intracellular hydrolysis initiates the formation of the hPL:GSH conjugate, which blocks the active site of and inhibits GSTP1 and thereby cancer cell proliferation."
Westover notes that “There are a lot of studies on both cell lines that are grown in Petri dishes and in animals that show that piperlongumine has anticancer effects. It can shrink tumors, it can kill cancer cells, but it's just not as potent as we would like, so a lot of effort has gone into trying to improve the potency of these compounds, make it so you only have to use a little bit to get the effect you want.”
The study, titled "Structural and Biochemical Analyses Reveal the Mechanism of Glutathione S-Transferase Pi 1 Inhibition by the Anti-cancer Compound Piperlongumine," is published in the Journal of Biological Chemistry. The work was supported by the V Foundation for Cancer Research (which was founded by ESPN and legendary basketball coach Jim Valvano), The Welch Foundation and the Cancer Prevention and Research Institute of Texas.

Kelsey Kaustinen

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