Insects and fungi trying to invade the Australian desert tree Acacia victoriae face a hidden threat. The plant’s seeds grow in pods that harbor chemicals capable of biological havoc.
Researchers now report that these chemicals, called avicins, may have medical uses. In mammals, the substances cause abrupt cell death and hinder inflammation, a basic weapon of the immune system. Two studies in the Sept. 25 Proceedings of the National Academy of Sciences (PNAS) suggest that avicins might be harnessed to redirect their power against tumors and the chronic inflammation that often precedes cancer.
In one study, researchers examined mouse skin to which they had regularly applied for up to 16 weeks cancer-causing chemicals from cigarette smoke. In unprotected cells, they saw inflammation and the hallmarks of cancer: DNA damage, uncontrolled cell proliferation, and eventually precancerous growths called papillomas.
When researchers applied avicins to the mice 15 minutes before each exposure to the carcinogens, the mice were one-third as likely to develop papillomas as untreated mice were. Microscopic analysis of skin cells revealed that avicins blocked inflammation, DNA damage, and cell proliferation, says Charles J. Arntzen, a plant molecular biologist at Arizona State University in Tempe, who coauthored both studies.
In the treated mice, avicins also blocked appearance of cancerous cells carrying a defective version of a gene called H-ras, which regulates cell growth. “Once H-ras mutates, the cell is transformed into a malignant condition and is no longer able to control its division,” he says. “We believe avicins target [such] transformed cells,” which then die before they can proliferate and form papillomas. Earlier test-tube experiments had shown that avicins trigger cell death in dividing cells.
Some scientists suspect that energy powerhouses, called mitochondria, change form in cancerous cells, says hematologist Jordan U. Gutterman of the University of Texas M.D. Anderson Cancer Center in Houston, who also coauthored both studies. Avicins may induce aberrant mitochondria to unleash the self-destruct signal, he says.
Another explanation may be that by limiting DNA damage, avicins prevent mutations from forming in the first place, Gutterman says.
In the other study, the scientists looked to see how avicins block inflammation. In a laboratory dish, they mixed one form of avicin with cancerous white blood cells that had been induced to release inflammatory agents.
The avicin inhibited production of several of these compounds. One is a protein known as nuclear transcription factor-kappa B, or NF-kappa B. It binds to cells’ DNA during inflammation and activates genes that trigger the production of various other inflammatory compounds, says Gutterman.
Problems occur when compounds that normally control release of NF-kappa B become disabled, and NF-kappa B is produced continuously, as can happen in damaged cells, he says. This can result in chronic inflammation.
In the cancerous white blood cells, the avicin kept NF-kappa B from binding to DNA. This reduced concentrations of two inflammatory agents–inducible nitric oxide synthase and cyclooxygenase-2, or COX-2.
Much research has linked inflammation to cancer–for example, gastritis caused by Helicobacter pylori infection is associated with stomach cancer. “We’re going on the assumption that inflammation is a key element in the progress of cancer and that anything you can do to intervene in that [progression] is a good thing,” Arntzen says.
“These studies indicate that avicins could develop as important chemopreventive agents in many conditions,” says Carlo M. Croce of Thomas Jefferson University in Philadelphia in the same issue of PNAS.
“Both studies represent good-quality research,” says A. Venketeshwer Rao of the University of Toronto. But before scientists test this drug in cancer patients, they’ll need to establish concentrations at which avicins are toxic, he says.
“The cancer scenario can be visualized as a big jigsaw puzzle with many pieces that have to fit perfectly,” Rao says. “These studies are like a single piece of the puzzle–they do not provide the answer, but they contribute incrementally to our understanding.”