Marine toxins may be developed to cancer drugs
There are many toxic chemicals produced by vibrantly colored creatures from the depths of the South Pacific Ocean. These toxins potentially can act as powerful anti-cancer drugs, as per research findings from UW Madison biochemists and their Italian colleagues.
The research team has defined the structure of the toxins and provided a basic understanding that can be used to synthesize pharmaceuticals, according to a study published this week in the Proceedings of the National Academy of Sciences (PNAS).
"We've determined how this class of toxins interacts with actin," an important protein responsible for cellular structure and movement, says Ivan Rayment, a professor of biochemistry in the College of Agricultural and Life Sciences who worked with John Allingham, a postdoctoral fellow, on the study. "We're adding to fundamental understanding which will be taken up by others to simplify chemical synthesis of what could potentially be powerful cancer treatments."
The toxins, which are produced naturally by organisms that exist symbiotically on deep-sea sponges, work by disrupting the activity of actin, an abundant protein that gives structure to eukaryotic cells. "Actin forms long chains, or filaments, that are essential for cellular locomotion, division and growth," explains Allingham. "Because cancer cell masses grow faster than other cells in the body, actin provides an excellent target for drugs that could inhibit such rapid growth."
Simple marine organisms provide a promising source of natural anti-tumor compounds. Recent structural and functional studies reveal that many toxic marine macrolides utilize a common strategy for interacting with actin in the cytoskeleton of cancer cells. This provides constraints for the design of new pharmacological agents. (Art: H. Adam Steinberg; Nudibranch photo: Gary Cobb, Deep sea sponge, Reidispongia coerule.
Adds Allingham: "These marine toxins can knock out the lynchpins in these long chains or cap their ends and kill cancer cells. Moreover, initial work shows that even a low dose of these toxins can bring a significant response."
Prior to the study published in PNAS, it was known that the marine toxins affect several forms of cancer - but not how they worked, says Rayment. The recent findings will enable the toxins to be synthesized in 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 to know how the natural compound works," he says. "Scientists who study natural 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 drugs might one day rival the success of Taxol, a powerful drug derived from a natural product that keeps breast-cancer cells from dividing.
"Actin-based drugs have not yet been used as successful drugs as have those that target microtubules, like Taxol, in part because we haven't understood how to target actin," Rayment explains.
Rayment and Allingham collaborated with Angela Zampella and Maria Valeria D'Auria at the Universita degli Studi di Napoli in Naples, Italy. The work was supported in part by a Canadian Institutes of Health Research Fellowship, a grant from the National Institutes of Health and the state of Wisconsin.