Anti-cancer possibilities seen for certain monoamine oxidase inhibitors
— In 2005, professor Ramin Shiekhattar, Ph.D., at The Wistar Institute
and his colleagues reported details about an enzyme involved in
appropriately repressing sets of neuronal genes in non-neuronal cells.
At the time, the scientists noted that the enzyme appeared to fit into
the same extended enzyme family that includes monoamine oxidases,
psychoactive enzymes that oxidize dopamine and norepinephrin.
Inhibitors of these enzymes have long been used to treat depression,
certain other psychiatric and emotional disorders, and Parkinson's
Now, in a study published online today in the June 26
issue of Chemistry & Biology, Shiekhattar and his team show that
the enzyme is itself a target for certain monoamine oxidase inhibitors
used to treat depression. One member of this family of drugs in
particular, called tranylcypromine (brand name Parnate®, manufactured
by GlaxoSmithKline), was seen to inhibit the enzyme most strongly. The
findings suggest that these anti-depressive drugs may have additional
applications in other medically relevant areas.
Shiekhattar notes that the enzyme studied exists in a complex with
another type of gene-regulating enzyme that has been implicated in the
development of cancer. Inhibitors of that second enzyme are currently
in clinical trails as cancer therapies.
monoamine oxidase inhibitors, currently used primarily to treat
depression, have anti-cancer activity too?" Shiekhattar says. "Our
findings indicate this could be the case, and we are currently
screening these drugs against many different types of cancer to answer
Because the primary role of the enzyme is to
repress sets of related genes, many other areas of potential influence
for the monoamine oxidase inhibitors are possible too, according to
Shiekhattar. At the very least, he says, the drugs will likely prove to
be useful laboratory tools for answering fundamental questions about
The enzyme in question is called
BHC110/LSD1, and it was the first human histone demethylase identified.
The enzyme's function is to remove methyl groups from small molecules
called histones to modify them in ways that trigger gene repression.
The second enzyme found in complex with BHC110/LSD1, acts in a similar
way. Called a deacetylase, this enzyme removes acetyl groups from
histones to repress gene expression.
In the body's scheme for
safely storing genes away until needed, DNA is tightly looped around
the histones, kept secure by enzymes similar to the ones studied by the
Wistar team until made accessible by the activity of other enzymes
responsible for gene expression. Eight histones comprise a nucleosome,
and long strings of nucleosomes coil in turn into chromatin, the basic
material of chromosomes.
The Wistar Institute. June 2006.