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Biological Chemistry

Cisplatin Hitches A Ride On RNA

Cancer Drugs: More of the medicine lands on cellular RNA than on DNA

by Sarah Webb
November 1, 2011

The widely used chemotherapy drug cisplatin kills cancer cells by latching onto DNA and gumming up DNA replication and transcription. But that may not be the full story. Now researchers demonstrate that a cell’s RNA accumulates up to 20 times more of the drug than does the cell’s DNA (ACS Chem. Biol., DOI: 10.1021/cb200279p).

Researchers have started to realize that cancer drugs often have multiple ways of doing their jobs, says Paul Hergenrother of the University of Illinois, Urbana-Champaign, who was not involved in the research. “Things aren’t as simple as they might seem,” he says. The multiple mechanisms may even account for a molecule’s effectiveness as a cancer drug, he adds.

RNA Goes Platinum
Credit: Erich G. Chapman
Cisplatin can accumulate on RNA, as shown in this model.
Credit: Erich G. Chapman
Cisplatin can accumulate on RNA, as shown in this model.

For decades, chemists have studied the complexes that cisplatin forms with DNA. The platinum-containing molecule forms covalent links that bridge two purine bases, usually guanines, within a single DNA strand. Victoria DeRose and her colleagues at the University of Oregon wanted to compare cisplatin’s interactions with DNA to those with another nucleic acid, RNA.

The researchers studied yeast cells because, like cancer cells, they’re eukaryotes and they divide rapidly. The team treated cultures of yeast cells with cisplatin and then isolated RNA and DNA from the resulting dead cells. The scientists next used mass spectrometry to measure how much platinum accumulated on the nucleic acids. On a per-nucleotide basis, the drug bound to DNA three times more often than to RNA. However, yeast cells contain 10 to 50 times more RNA than DNA, so most of the cisplatin landed on RNA. The researchers estimated that the cells’ accumulation of platinum on RNA outpaced the accumulation on DNA by between fourfold and 20-fold.

DeRose says she was surprised by that result because RNA turns over rapidly within living cells. “We thought that the platinated RNAs wouldn’t build up because the cell would just degrade them,” she says.

A majority of the platinum molecules latched onto RNA in the ribosome. The researchers also identified a few sites on the ribosome that the drug bound to.

Hergenrother says that the results point to an area for researchers to explore further, especially understanding the role of these platinum-RNA interactions in the activity of cisplatin.

DeRose and her colleagues plan to look for more RNA binding sites for cisplatin in yeast and to confirm their findings in human cancer cells. They also want to understand whether cisplatin binding changes the activity of the ribosome or of other RNA molecules.



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