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
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,
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."
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, which 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 these 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 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 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 Johns 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 Johns Hopkins
Technology Transfer Office, they have filed an application
for a U.S. patent covering this class of compounds.
Along with Sampathkumar and Yarema, the co-authors of
the journal article include several past and present Johns
Hopkins students: Mark B. Jones, M. Adam Meledeo,
Christopher T. Campbell, Sean S. Choi, Kaoru Hida, Prasra
Gomutputra and Anthony Sheh. Other co-authors were Tim
Gilmartin and Steven R. Head, both of the DNA Microarray
Facility of the Consortium for Functional Glycomics at the
Scripps Research Institute in La Jolla, Calif.
Funding for this research was provided by the Arnold
and Mabel Beckman Foundation, the National Institutes of
Health and the National Science Foundation.