The molecule, lomaiviticin A, was previously shown to be lethal to cultured human cancer cells, but the mechanism of its operation remained unsolved for well over a decade.
In a series of experiments, Yale scientists Seth Herzon, Peter Glazer, and colleagues show that the molecule nicks, cleaves, and ultimately destroys cancer cells’ DNA, preventing replication.
“DNA is one of the primary targets of anticancer agents, and cleavage of both DNA chains is the most potent form of DNA damage,” said Herzon, professor of chemistry.
Herzon’s team tested and distinguished the effects of lomaiviticin A-which is produced by a marine bacterium associated with sea squirts-and two closely related molecules, lomaiviticin C and kinamycin C, which are also produced by bacteria.
The scientists evaluated and contrasted their effects on cancer cells’ growth and DNA. They found that the two diazofluorenes of lomaiviticin A are intimately involved in DNA cleavage, and that the loss of one diazofluorene profoundly diminishes the ability of the molecules to kill cells, Herzon said.
“Our data support a model for DNA cleavage involving breakage of both strands of DNA by a single molecule of lomaiviticin,” he said.
“The best way to think about this is as if lomaiviticin A were a garden shear and the two strands of DNA were the vines you are trimming. As you would grasp the vines and cut two of them to the same length, lomaiviticin A interacts with DNA and then snips the strands at the same site.”