Nanofibers made of copper-binding peptides disrupt copper homeostasis in cancer cells
While toxic in high concentrations, copper is essential to
life as a trace element. Many tumors require significantly more copper
than healthy cells for growth—a possible new point of attack for cancer
treatment. In the journal Angewandte Chemie, a research team from
the Max Planck Institute for Polymer Research has now introduced a novel
method by which copper is effectively removed from tumor cells, killing
them.
© Wiley-VCH, re-use with credit to 'Angewandte Chemie' and a link to the original article.
Copper is an essential cofactor for a variety of enzymes
that play a role in the growth and development of cells. For example,
copper ions are involved in antioxidant defense. Cells very strictly
regulate the concentration and availability of copper ions. On the one
hand, enough copper ions must be on hand; on the other, the
concentration of free copper ions in the cytoplasm must be kept very low
to avoid undesired side effects. Extracellular, doubly charged copper
ions are reduced to singly charged copper, transported into the cell,
stored in pools, and transferred to the biomolecules that require them
on demand. To maintain the cellular copper equilibrium (homeostasis),
cells have developed clever trafficking systems that use a variety of
transporters, ligands, chaperones (proteins that help other complex
proteins to fold correctly), and co-chaperones.
Because cancer cells grow and multiply much more rapidly,
they have a significantly higher need for copper ions. Restricting their
access to copper ions could be a new therapeutic approach. The problem
is that it has so far not been possible to develop drugs that bind
copper ions with sufficient affinity to “take them away” from
copper-binding biomolecules.
In cooperation with the Stanford University School of
Medicine (Stanford/CA, USA) and Goethe University Frankfurt/Main
(Germany), Tanja Weil, Director of the Max Planck Institute for Polymer
Research (Mainz) and her team have now successfully developed such a
system. At the heart of their system are the copper-binding domains of
the chaperone Atox1. The team attached a component to this peptide that
promotes its uptake into tumor cells. An additional component ensures
that the individual peptide molecules aggregate into nanofibers once
they are inside the tumor cells. In this form, the fiber surfaces have
many copper-binding sites in the right spatial orientation to be able to
grasp copper ions from three sides with thiol groups (chelate complex).
The affinity of these nanofibers for copper is so high that they also
grab onto copper ions in the presence of copper-binding biomolecules.
This drains the copper pools in the cells and deactivates the
biomolecules that require copper. As a consequence, the redox
equilibrium of the tumor cell is disturbed, leading to an increase in
oxidative stress, which kills the tumor cell. In experiments carried out
on cell cultures under special conditions, over 85 % of a breast cancer
cell culture died off after 72 hours while no cytotoxicity was observed
for a healthy cell culture.
The research team hopes that some years in the future,
these fundamental experiments will perhaps result in the development of
useful methods for treating cancer.
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About the Author
Prof. Dr. Tanja Weil is a director of
the Max Planck Institute for Polymer Research, heading the division
"Synthesis of Macromolecules". Her scientific interests focus on
innovative synthesis concepts to achieve functional macromolecules and
hybrid materials to solve current challenges in biomedicine and material
science.
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