Cancer drug sticks to RNA like glue

Cancer drug sticks to RNA like glue

U. OREGON (US) - A common cancer drug binds quickly and firmly to RNA, a finding that has the potential to open new targets for drug delivery with fewer toxic side effects, a new study shows.

Researchers have long known that cisplatin, a platinum compound used to fight tumors in nearly 70 percent of all human cancers, attaches to DNA, but its attachment to RNA was thought to be fleeting, says Victoria J. DeRose, professor of bioinorganic chemistry, biophysical chemistry, and chemical biology at the University of Oregon, who decided to take a closer look due to recent discoveries of critical RNA-based cell processes.

"We're looking at RNA as a new drug target," she says. "We think this is an important discovery because we know that RNA is very different in tumors than it is in regular healthy cells. We thought that the platinum would bind to RNA, but that the RNA would just degrade and the platinum would be shunted out of the cell.
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"In fact, we found that the platinum was retained on the RNA and also bound quickly, being found on the RNA as fast as one hour after treatment."

For the study published online in the journal ACS Chemical Biology, DeRose and colleagues applied cisplatin to rapidly dividing and RNA-rich yeast cells (Saccharomyces cerevisiae, a much-used eukaryotic model organism in biology). The DNA and RNA were then extracted from the treated cells and the researchers studied the density of platinum per nucleotide with mass spectrometry.

Specific locations of the metal ions were further hunted down with detailed sequencing methods. The researchers found that the platinum was two to three times denser on DNA but there was a much higher whole-cell concentration on RNA. Moreover, the drug bound like glue to specific sections of RNA.

"Can this drug be made to be more or less reactive to specific RNAs?" DeRose asks. "Might we be able to go after these new targets and thereby reduce the drug's toxicity?"

While cisplatin is effective in reducing tumor size, its use often is halted because of toxicity issues, including renal insufficiency, tinnitus, anemia, gastrointestinal problems, and nerve damage.

RNA's roles have come under intense scrutiny since completion of the human genome opened new windows on DNA. It had been assumed that RNA was simply a messenger that coded for protein activity. New technologies, DeRose says, have shown that a vast amount of RNA performs an amazing level of different functions in gene expression, controlling it in specific ways during development or disease, particularly in cancer cells.

For the study, DeRose's team only explored cisplatin's binding on two forms of RNA: ribosomes, where the highest concentration of the drug was found; and messenger RNA. There are more areas to be looked at, says DeRose, whose group initially developed experience using and mapping platinum's activity as a mimic for other metals in her research on RNA enzymes.

DeRose is now planning work with colleague Hui Zong, a biologist studying how cancer emerges, to extend the research into mouse cells to see if the findings in yeast RNA hold up.

An additional collaboration with chemist Michael Haley involves the creation of new platinum-based drugs with "reaction handles" that will allow researchers to easily pull the experimental drugs out of cells, while still attached to their biological targets.

The research was funded in part by the National Institutes of Health.

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