Areca nuts, also called betel nuts, contain a stimulant compound called arecoline, which has been found to have anticancer properties. [NIH]
Areca nuts, also called betel nuts, contain a stimulant compound called arecoline, which has been found to have anticancer properties. [NIH]

“All things are poison, and nothing is without poison—only the dose makes a thing not a poison,” reads the familiar adage from the 15th century Swiss-German, physician, philosopher, and founder of toxicology, Paracelsus. Researchers have known for centuries that commonly toxic substances can also make useful tools when studying disease, and in some instances can even be used in small enough doses as a treatment regimen.   

Investigators at the Winship Cancer Institute of Emory University, following Paracelsus mantra, have just discovered that a compound, which has been linked to oral and esophageal cancer, contained within areca nuts also seems to have anticancer properties. Arecoline is the stimulant component of areca nuts, which are often sought after and chewed for their stimulant effects in many Asian countries. 

Analogous to nicotine, arecoline was identified as an inhibitor of the enzyme mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1), which contributes to the metabolism-distorting Warburg effect in cancer cells. The Warburg effect, named after 1931 Nobel laureate Otto Warburg, describes how cancer cells tend to favor the inefficient use of glucose, known as glycolysis, and de-emphasize their mitochondria. Cancer cells benefit from this metabolic distortion because the byproducts of glycolysis can be utilized as building blocks for fast growth.

“This is just a proof of principle, showing that ACAT1 is a good anticancer target,” remarked senior study investigator Jing Chen, Ph.D., professor of hematology and medical oncology at Emory University School of Medicine and Winship Cancer Institute. “We view arecoline as a lead to other compounds that could be more potent and selective.”

The findings from this study were published recently in Molecular Cell in an article entitled “Tetrameric Acetyl-CoA Acetyltransferase 1 Is Important for Tumor Growth.”

The Emory researchers noted that arecoline could be compared to arsenic, a form of which is used as a treatment for acute promyelocytic leukemia but is also linked to several types of cancer. Plus, arecoline's cancer-promoting effects may be limited if it is not delivered or absorbed orally.

When arecoline first arose in a chemical screen, Dr. Chen noted that “it sounded like a carcinogen to me. But it all depends on the dose and how it is taken into the body.” Paracelsus would have been in agreement.

Dr. Chen’s laboratory had previously identified the mitochondrial thiolase ACAT1 enzyme as a control valve for regulating the Warburg effect. In their earlier work, the researchers showed that ACAT1 enzymatic activity was higher in several types of cancer cells, even though the levels of ACAT1 protein were about the same. They scientists surmised that the protein clusters together as tetramers in cancer cells. Tyrosine kinases, often on overdrive in cancer cells, “hijack” ACAT1 and nudge it into tetramers, which are enzymatically more active.

Yet arecoline, identified in a screen of 2000 FDA-approved small-molecule compounds, can inhibit ACAT1 and prevent it from forming tetramers. Arecoline forms a chemical bond with a part of the ACAT1 protein, the researchers showed. Moreover, arecoline appears to do what the researchers proposed it would—steering the cell’s metabolism away from glycolysis. The compound inhibited the growth of human lung cancer and leukemia cells both in culture and grafted into mice, without affecting the growth of healthy blood cells.

ACAT1 seems to lead a double life within cells. It breaks down ketones and the amino acid isoleucine, and it also modifies other proteins through acetylation, which is how it regulates the Warburg effect.

Genetic mutations in ACAT1 lie behind a very rare metabolic disorder called beta-ketothiolase deficiency, and complete inhibition of ACAT1 could induce side effects resembling the disorder. However, when the Emory team incompletely “knocked down” ACAT1 in cells using arecoline or genetic tools, the authors found that the main effect was on protein acetylation, not on ketone metabolism.

While the researchers did not see overt toxicity when treating mice with arecoline, more extensive pharmacokinetic and toxicology studies with arecoline and similar compounds are needed.