A toxin derived from a reclusive sea creature resembling a translucent doughnut has inspired UT Southwestern Medical Center researchers to develop a related compound that shows promise as a cancer treatment.
In a study appearing online this week in the Proceedings of the National Academy of Sciences, the UT Southwestern scientists detail how the toxin blocks uninhibited reproduction of cultured human cancer cells while leaving healthy cells unaffected.
An accompanying study in PNAS shows that, in pre-clinical trials, a synthetic form of the toxin reduced human tumors implanted in mice without the harmful side effects seen using other cancer drugs.?Diazonamide is a special molecule ? it?s teaching us more than we imagined,? said Dr. Patrick Harran, professor of biochemistry and a senior author on both studies.
?This is a truly exciting result,? said Dr. John Schwab, a program officer at the National Institutes of Health?s National Institute of General Medical Sciences, which partly funded the work. ?Not only has this UT Southwestern team identified a potent anti-cancer drug, but its unique mode of action avoids the kinds of side effects that make cancer chemotherapy so difficult. It?s a great example of how NIH support for fundamental chemical research can benefit the American health-care consumer.?
The animal, Diazona angulata, is a sea squirt a few inches wide that lives in colonies anchored to rocks. It was discovered offshore of the Philippines in 1990 as scientists were looking for species that might lead to useful drugs. From a few specimens, scientists extracted a tiny amount of a toxin, diazonamide A, which the animal probably uses to repel predators.
The toxin proved to kill cancer cells in culture, but so little of its natural form was available that a race soon began to synthesize it in the laboratory.
A chemical structure for diazonamide A was published in 1991, but in 2001, Dr. Harran?s group showed that initial report to be incorrect, and uncovered the correct structure. In the first of the two new studies, Dr. Harran and his co-workers synthesized several variants of diazonamide A in order to pin down how it prevents cancer cells from dividing.
Normal cell division involves a structure called the mitotic spindle, which pulls apart the chromosomes before the cell splits. The spindle is primarily made out of a substance called tubulin. Some anti-cancer drugs attack tubulin, but they have serious side effects, such as nerve damage and depletion of bone marrow and white blood cells.
The UT Southwestern researchers found that while diazonamide A blocked cell division, it seemed not to bind directly to tubulin. Instead, Dr. Xiaodong Wang, professor of biochemistry, and Dr. Gelin Wang, instructor of biochemistry, found that the toxin interacted with an enzyme called OAT, which was known to be involved in cellular metabolism but had no previously known role in cell division.
Joyant Pharmaceuticals, a Dallas-based company founded by Drs. Harran and Wang, has licensed the rights from UT Southwestern to develop diazonamide and its analogs as anti-cancer drugs. It is researching a manufacturing process and putting the molecule through pre-clinical screening.