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How does the antitumor drug get
to the cell nucleus?
Reported November 05, 2007
In the journal Angewandte Chemie, they present their
hypothesis about the transport mechanism.
It has always been assumed that cisplatin simply passes through the cell
membrane; however, growing evidence indicates that a copper transporter is
involved. Ctr1 is a membrane-dwelling protein that brings copper into cells.
It consists of three helical segments that sit in the membrane, one end
protruding into the cell, the other on the outside. Three such molecules
lodge together to form a channel-like structure. The end that sticks out of
the cell and the interior of the "channel contain many sulfur-containing
methionine groups, which are important for binding copper.
A team led by Giovanni Natile at the University of Bari (Italy) has now
proven that this structural element also plays a role in binding platinum.
The researchers produced a synthetic peptide with a structure very similar
to the extracellular end of the copper transport protein. Cisplatin is a
complex with a central platinum ion and four ligands: two neighboring amino
groups and two neighboring chloride ions. The peptide displaces all four of
these ligands and binds to the platinum ion itself.
As is the case for copper, the transport protein seems to bind the platinum
atom from cisplatin by replacing all other ligands bound to the metal ion.
The next step could be the traversal of a ligand-free "naked platinum atom
through the channel and into the cytosol of the cell. However, this
contradicts other experiments that have demonstrated that treated tumor
cells do not contain bare platinum, but rather undegraded cisplatin-accumulated
in certain organelles.
Natile and his co-workers have proposed an interesting hypothesis to explain
these observations: After an initial interaction between a few cisplatin
molecules and the methionine-rich extracellular end of the copper
transporter, the platinum ion does not pass through the channel, but instead
stabilizes the trimeric channel structure. This sets in motion a mechanism
called endocytosis, in which the cell membrane encircles the transporter and
forms a little interior bubble filled with the outer medium. This medium
contains some intact cisplatin. The bubble then migrates to the interior of
the cell and comes into contact with the organelles, including the nucleus.
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