Fight Aging!

In order to achieve meaningful progress in our lifetimes, the future of cancer therapy must become driven by a focus on common features that occur in all or near all cancers, and which are fundamental to the biology of cancer. Approaching the biochemistry of cancer in any other way leads to therapies that are only relevant to a small fraction of all cancers, targeting mechanisms that a tumor cell population is quite capable of evolving away from, given the selection pressure applied by the treatment. There are only so many researchers and only so much research funding. To find success in controlling cancer as a class of disease, future cancer therapies must have the potential to be very broadly applicable, to need minimal changes or no changes in delivery to target different forms of cancer.

Cancerous cells replicate rapidly. Biochemical differences in cancer cells that are an inevitable consequence of a fast pace of replication seem likely to be a fruitful place to look for ways to attack the more severe forms of cancer. In today's research materials, scientists discuss one of these line items, which is that cells require copper to function, but cancerous cells deplete their copper reserves as a result of rampant replication. Finding ways to temporarily further deplete the available copper in cancerous cells can lead to their destruction. It is a simple concept, but as noted here, has proven to be challenging to implement in practice.

Tumor Cells Suffer Copper Withdrawal

While toxic in high concentrations, copper is essential to life as a trace element. 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.

Researchers 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.

Chaperone-Derived Copper(I)-Binding Peptide Nanofibers Disrupt Copper Homeostasis in Cancer Cells

Copper (Cu) is a transition metal that plays crucial roles in cellular metabolism. Cu+ homeostasis is upregulated in many cancers and contributes to tumorigenesis. However, therapeutic strategies to target Cu+ homeostasis in cancer cells are rarely explored because small molecule Cu+ chelators have poor binding affinity in comparison to the intracellular Cu+ chaperones, enzymes, or ligands. To address this challenge, we introduce a Cu+ chaperone-inspired supramolecular approach to disrupt Cu+ homeostasis in cancer cells that induces programmed cell death.

The Nap-FFMTCGGCR peptide self-assembles into nanofibers inside cancer cells with high binding affinity and selectivity for Cu+ due to the presence of the unique MTCGGC motif, which is conserved in intracellular Cu+ chaperones. Nap-FFMTCGGCR exhibits cytotoxicity towards triple negative breast cancer cells, impairs the activity of Cu+ dependent co-chaperone super oxide dismutase1 (SOD1), and induces oxidative stress. In contrast, Nap-FFMTCGGCR has minimal impact on normal HEK 293T cells. Control peptides show that the self-assembly and Cu+ binding must work in synergy to successfully disrupt Cu+ homeostasis. We show that assembly-enhanced affinity for metal ions opens new therapeutic strategies to address disease-relevant metal ion homeostasis.