Nutty Anticancer Tool

The stimulant component of areca nuts, arecoline, has anticancer properties, according to the researchers at Winship Cancer Institute of Emory University.  These particular findings will be published in Molecular Cell.

In many Asian countries the areca nuts are chewed for their stimulant effects.  Evidence links this practice to the development of oral and esophageal cancer. Arecoline is analogous to nicotine and identified as an inhibitor of the enzyme ACAT1 that contributes to the metabolism-distorting Warburg effect in cancer cells.

The health news observers have complained that= coffee, for instance, is implicated in causing cancer in one week, and then absolved the next.  Senior author Jin Chen, PhD, professor of hematology and medical oncology at Emory University School of Medicine and Winship Cancer Institute, stress that the same trend is not the same for arecoline.  Showing that ACAT1 is a good anticancer target is just a proof of principle and they view arecoline as a lead to other compounds that could be more potent and selective.

According to Chen arecoline could be compared to arsenic, which is a form used as a treatment for acute promyelocytic leukemia, but is also linked to several types of cancer.  If not delivered or absorbed orally, arecoline’s cancer-promoting effects may be limited.

When arecoline first came to light in a chemical screen, it sounded like a carcinogen to Chen, but it all depends on the dose and how it is taken into the body.  

The Warburg effect from 1931 describes how cancer cells tend to favor the inefficient use of glucose, also known as glycolysis, and de-emphasizes their mitochondria.  This metabolic distortion benefits the cancer cells because the byproducts of glycolysis can be used as building blocks for fast growth.

In the lab, Chen had previously identified the mitochondrial thiolase ACAT1 as a control valve regulating the Warburg effect.  Researchers showed that ACAT1 enzymatic activity was higher in several types of cancer cells, even though the levels of ACAT1 protein are about the same.  This is because the protein clusters together as tetramers in cancer cells and when tyrosine kinases are on overdrive in cancer cells, they hijack ACAT1 and nudge it into tetramers that are enzymatically more active.  Arecoline appears to steer cells’ metabolism away from glycolysis.

There seems to be a double role for the enzyme ACAT1 as 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.

ACAT1 has genetic mutations that lie behind a very rare metabolic disorder called beta-ketothiolase deficiency.  Complete inhibition of this could induce side effects resembling that disorder, but the main effect was on protein acetylation and not on ketone metabolism.

There appeared to be no obvious toxicity when treating mice with arecoline but more extensive pharmacokinetic and toxicology studies with arecoline and similar compounds are needed.

Dr Fredda Branyon