Cornell researchers find common chemotherapy drug stops enzymes that lead to cancer cell growth

Cornell University research has found that a commonly used chemotherapy drug called, etoposide, stops enzymes that lead to cancer cells growing.

According to a report by the Cornell Chronicle, the drug stalls and poisons the enzymes that make cancer cells grow. 

The study was led by Michelle Wang, the James Gilbert White Distinguished Professor of the Physical Sciences and Howard Hughes Medical Institute investigator in the College of Arts and Sciences. 

The paper was titled “Etoposide promotes DNA loop trapping and barrier formation by Topoisomerase II” and was published in Nature Chemical Biology on Jan. 30. It is believed that the study will help the development of cancer inhibitors and screening tools for identifying drug mechanisms that can improve treatment for patients.

“We normally ask, what is the best way to study molecular machineries that take place on DNA?” Wang said in the Cornell Chronicle report. “To understand how those enzymes work, we want to mimic what might be happening in the cell. Motor proteins pull on the DNA or apply a force on the DNA. We said, 'OK, we can apply a force and see what happens.'”

According to the report, the drug works by targeting Type IIA eukaryotic topoisomerases, which are enzymes that enable replication of cancer cells. Topo IIs perform an “elaborate kind of rope trick” that relaxes the DNA by cutting it and then passing another strand through its middle, and reconnecting the cut DNA. This happens without damaging the DNA’s often-delicate genetic structure. 

Etoposide stabilizes a DNA double-stranded break before the reconnection, which prevents cancer cells from replicating. The team found how etoposide interacts with the DNA structure. The team used three single molecule manipulation tactics to study how the drug has an effect on the three Topo IIs, which were provided by collaborators led by professor James Berger of Johns Hopkins University. 

The researchers used optical tweezers to stretch the DNA and show how the drug compacts, releases and breaks it. The team learned that etoposide could convert Topo II into a “strong roadblock of DNA processing machineries.”

The team now has a system for showing how other topoisomerase drugs work by finding various ways etoposide works against the Topo II. Wang said this gives the team a set of tools to study a variety of topoisomerases and other drugs comprehensively.

The research for the project was supported by the National Institutes of Health and the Howard Hughes Medical Institute.