Hybrid Molecule Cause Cancer Cells to Self-Destruct

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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

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By joining a sugar to a short-chain fatty acid compound, s

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 s Hopkins team

tried a different tack. " We didn't think they chose the right

partner molecule, " said 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. "

The researchers focused on a sugar called N-acetyl-D-mannosamine, or

ManNAc, for short. The team created a hybrid molecule by linking

ManNAc with butyrate. The hybrid easily penetrates a cell's surface,

then is split apart by enzymes inside the cell. Once inside the

cell, ManNAc is processed into another sugar known as sialic acid

that plays key roles in cancer biology, while butyrate orchestrates

the expression of genes responsible for halting the uncontrolled

growth of cancer cells.

Although the study of the exact molecular mechanism is in its early

stages, the researchers believe the separate chemical components

work together to bolster the cancer-fighting power of butyrate. The

double attack triggers cellular suicide, also called apoptosis, in

the cancer cells.

To find out whether this butyrate-ManNAc hybrid alone would produce

the positive results, the researchers tested three other sugar-

butyrate combinations and a butyrate salt compound with no sugar

attached. The four other formulas and the butyrate-ManNAc hybrid

were each added to lab dishes containing cancer cells. After three

to five days, cancer growth had slowed in all of the dishes. After

15 days, however, cancer growth had resumed in dishes treated with

four of the compounds. But in samples treated with the butyrate-

ManNAc hybrid, all of the cancer cells had died.

The researchers also wanted to find out whether administering the

two parts of the hybrid independently would achieve the same result.

But in these experiments, the cancer cells did not self-destruct.

The researchers suspect this is because the hybrid molecules more

easily penetrate the surface of the cell than the individual

chemicals. Once the components are inside, the researchers believe

the partners help enzymes to resume the normal assembly of sugar

molecules and correct aberrant gene expression patterns, two

processes that go awry when cancer occurs.

Now that they've identified the butyrate-ManNAc molecule as a

potential cancer fighter, the s Hopkins team members are

expanding their research, looking for new drug-delivery methods and

preparing for animal testing. The researchers believe the hybrid

molecule will have minimal effect on healthy cells. Through the

s Hopkins Technology Transfer Office, they have filed an

application for a U.S. patent covering this class of compounds.