sugar and fatty acid combo may provide one-two punch vs cancer(Johns Hopkins)

[Lani]

Hybrid Molecule Causes Cancer Cells to Self-Destruct: Lab Tests of Sugar and Short-Chain Fatty Acid Combo Point to New Strategy to Combat Disease [Johns Hopkins University]
By joining a sugar to a short-chain fatty acid compound, Johns Hopkins researchers have developed a two-pronged molecular weapon that kills cancer cells in lab tests. The researchers cautioned that their double- punch molecule, described in the December issue of the journal Chemistry & Biology, has not yet been tested on animals or humans. Nevertheless, they believe it represents a promising new strategy for fighting the deadly disease.

"For a long time, cancer researchers did not pay much attention to the use of sugars in fighting cancer," said Gopalan Sampathkumar, a postdoctoral fellow in the university's Department of Biomedical Engineering and lead author of the journal article. "But we found that when the right sugar is matched with the right chemical partner, it can deliver a powerful double-whammy against cancer cells."

Sampathkumar and his colleagues built upon 20-year-old findings that a short-chain fatty acid called butyrate can slow the spread of cancer cells. In the 1980s, researchers discovered that butyrate, which is formed naturally at high levels in the digestive system by symbiotic bacteria that feed on fiber, can restore healthy cell functioning.

Efforts to use butyrate as a general drug for tumors elsewhere in the body, however, have been hindered by the high doses of the compound needed to effectively eradicate cancer. To get around this problem, scientists have tried to make butyrate more potent by modifying it or joining it to other compounds. Usually, the results have been disappointing because the molecular partner added to butyrate to improve delivery to the cancer cells often produced unsafe side effects.

In some of the less successful experiments, designed to avoid toxic side effects, researchers used innocuous sugar molecules such as glucose to carry butyrate into the cells. The Johns Hopkins team tried a different tack. "We didn't think they chose the right partner molecule," said Kevin J. Yarema, an assistant professor of biomedical engineering who supervised the project. "Our insight was to select the sugar partner to serve not just as a passive carrier but as additional ammunition in the fight against cancer."




ABSTRACT: Targeting Glycosylation Pathways and the Cell Cycle: Sugar-Dependent Activity of Butyrate-Carbohydrate Cancer Prodrugs [Chemistry & Biology]
Short-chain fatty acid (SCFA)-carbohydrate hybrid molecules that target both histone deacetylation and glycosylation pathways to achieve sugar-dependent activity against cancer cells are described in this article. Specifically, n-butyrate esters of N-acetyl-d-mannosamine (But4ManNAc, 1) induced apoptosis, whereas corresponding N-acetyl-d-glucosamine (But4GlcNAc, 2), d-mannose (But5Man, 3), or glycerol (tributryin, 4) derivatives only provided transient cell cycle arrest. Western blots, reporter gene assays, and cell cycle analysis established that n-butyrate, when delivered to cells via any carbohydrate scaffold, functioned as a histone deacetylase inhibitor (HDACi), upregulated p21WAF1/Cip1 expression, and inhibited proliferation. However, only 1, a compound that primed sialic acid biosynthesis and modulated the expression of a different set of genes compared to 3, ultimately killed the cells. These results demonstrate that the biological activity of butyrate can be tuned by sugars to improve its anticancer properties.