Structures Of Marine Toxins Provide Insight Into Their Effectiveness As Cancer Drugs

The research team has defined the structure of the toxins andprovided a basic understanding that can be used to synthesizepharmaceuticals, according to a study published this week in theProceedings of the National Academy of Sciences (PNAS).

"We've determined how this class of toxins interacts withactin," an important protein responsible for cellular structure andmovement, says Ivan Rayment, a professor of biochemistry in the Collegeof Agricultural and Life Sciences who worked with John Allingham, apostdoctoral fellow, on the study. "We're adding to fundamentalunderstanding which will be taken up by others to simplify chemicalsynthesis of what could potentially be powerful cancer treatments."

The toxins, which are produced naturally by organisms that existsymbiotically on deep-sea sponges, work by disrupting the activity ofactin, an abundant protein that gives structure to eukaryotic cells.

"Actin forms long chains, or filaments, that are essential for cellularlocomotion, division and growth," explains Allingham. "Because cancercell masses grow faster than other cells in the body, actin provides anexcellent target for drugs that could inhibit such rapid growth."

Adds Allingham: "These marine toxins can knock out the lynchpins inthese long chains or cap their ends and kill cancer cells. Moreover,initial work shows that even a low dose of these toxins can bring asignificant response."

Prior to the study published in PNAS, it was known that the marinetoxins affect several forms of cancer - but not how they worked, saysRayment. The recent findings will enable the toxins to be synthesizedin a lab instead of harvested from the depths of the ocean floor,meaning that the drugs can be engineered to be as effective as possible.

"In order to chemically synthesize a better drug, it is a good idea toknow how the natural compound works," he says. "Scientists who studynatural products take their cues from what nature has already done.We're adding deep biochemical meaning to this area."

He adds that synthetic chemists hope that actin-based drugsmight one day rival the success of Taxol, a powerful drug derived froma natural product that keeps breast-cancer cells from dividing.

"Actin-based drugs have not yet been used as successful drugsas have those that target microtubules, like Taxol, in part because wehaven't understood how to target actin," Rayment explains.

Rayment and Allingham collaborated with Angela Zampella and MariaValeria D'Auria at the Universita degli Studi di Napoli in Naples,Italy. The work was supported in part by a Canadian Institutes ofHealth Research Fellowship, a grant from the National Institutes ofHealth and the state of Wisconsin.