after treatment with etoposide
Credit: CNIO
A compound that interferes with the cell cycle can increase the antineoplastic effects of etoposide, according to research published in Cell Reports.
Etoposide works by inhibiting topoisomerase II (TOP2), a protein needed for DNA repair during cell division.
Researchers discovered a relationship between TOP2 and Cdh1, a protein that (along with Cdc20) controls cell division by activating the anaphase-promoting complex/cyclosome (APC/C).
So the team hypothesized that combining etoposide with a compound that inhibits Cdh1 might improve etoposide’s antineoplastic effects. Experiments in cancer cell lines confirmed this theory.
Marcos Malumbres, PhD, of the Spanish National Cancer Research Centre (CNIO) in Madrid, and his colleagues began this research by investigating Cdh1 in vitro and in mouse models.
The team found that a decrease in Cdh1 activity increases cells’ TOP2 levels. So they decided to combine etoposide with a Cdh1 inhibitor and evaluate the effect on cancer cells, which divide more than normal cells and therefore have a greater dependency on TOP2 to maintain DNA integrity.
The researchers tested proTAME, a small molecule that targets APC/C-Cdh1 and APC/C-Cdc20, in combination with etoposide. And they found the drugs had a synergistic effect against cancer cells.
In experiments with a lung cancer cell line (A549) and 2 breast cancer cell lines (HeLa and MCF7), administering proTAME and etoposide together proved more effective than administering either compound alone.
The researchers believe these findings could apply to other malignancies as well. Etoposide has demonstrated activity against a number of cancers, including leukemias, lymphomas, and multiple myeloma.
The team said their next step is to study the etoposide-proTAME combination in patients and investigate the malignancies in which this therapeutic strategy would be most effective.
The researchers also noted that previous studies have shown Cdh1 is inactive in some patients due to various oncogenic mutations. So stratifying patients according to their tumor’s Cdh1 status could optimize treatment with etoposide.
