Best kept apart

Drug therapies that combine TOP2 poisons and proteasome inhibitors may have unintended effects on cancer cells.
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Image showing distinct fragments of DNA, which have been labeled different colors, fusing together following treatment with TOP2 poisons. Image credit: Darawalee Wangsa (CC BY 4.0)

Molecules of DNA contain the archive of a cell’s genetic information and identity. DNA comprises two strands that twist together into a structure known as a double helix. Physical tension tends to build up in the double helix that can cause it to break apart. To avoid this, cells have an enzyme called Topoisomerase II (TOP2) that relieves the tension by attaching itself to DNA and breaking it in a controlled way before re-sealing the break.

Drugs known as TOP2 poisons stop TOP2 from working and trap it on the DNA, which may lead to cells accumulating DNA breaks and eventually dying. Cancer cells are particularly prone to acquiring breaks in their DNA, and TOP2 poisons are therefore often used as part of chemotherapy treatments for cancer. However, it remains unclear why TOP2 poisons are more effective at killing some types of cancer cells than others.

It is thought that a molecular machine, known as the proteasome, helps cells repair the damage caused by TOP2 poisons by removing the trapped TOP2 proteins and allowing DNA repair proteins access to the broken DNA underneath. Now, Sciascia et al. have used a genetic approach to study the relationship between the proteasome and DNA repair in mouse cells exposed to TOP2 poisons.

The experiments found that when the proteasome removed TOP2 proteins that had become trapped on DNA, the subsequent DNA repair was prone to errors. Pre-treating mouse cells with another drug that inhibited the proteasome protected the cells from the effects of the TOP2 poison. Once the TOP2 poison had left the cells, the previously trapped TOP2 proteins correctly fixed the DNA and detached as they would normally. As a result, cells that had been treated with a proteasome inhibitor were more likely to survive treatment with TOP2 poisons.

Since both TOP2 poisons and proteasome inhibitors are clinically approved drugs for treating cancer they can be, and already have been, tested for use together in combination drug therapies. However, these findings suggest that caution should be taken when using these drugs together, because instead of harming the cancer cells, the proteasome inhibitors may protect the cells from the toxic effects of TOP2 poisons.