Flies' taste for tumor-fighting compounds could aid drug discovery

FThousands of years ago, people likely learned about herbal remedies by observing the behavior of other animals. The Navajo people credit brown bears with leading them to the Osha root (Ligusticum porteri), which they use to relieve headaches, treat infections or repel insects.¹ An Asian legend says that you can watch mongooses chewing Rauvolfia serpentina Leaves, before fighting with cobras, people discovered their use as an antidote to snake bites.² Although it is not possible to verify these folk tales, their abundance suggests that animal self-medication has influenced human medical knowledge.

Studying fruit flies in the lab could also inspire new cancer drugs, according to a new study Current Biology.³ A team led by neuroscientist Craig Montell of the University of California, Santa Barbara, found that flies with intestinal tumors consumed a particular bitter chemical more often than healthy flies, which normally rejected it. Ingestion of this compound had a strong, sustained antitumor effect in these flies, suggesting a possible self-medication strategy that could guide drug development.

Because flies rarely develop cancer due to their short lifespans, the team artificially created three cancer-like models to test whether tumors influenced the flies' preference for different compounds. Using three different transgenes, they caused the insects' intestinal stem cells to multiply and develop tumor-like properties. The researchers then had tumor-bearing and healthy flies choose between sucrose alone or a mixture of sucrose and one of four bitter substances, including caffeine and the plant compound aristolochic acid (ARI). By measuring how often flies fed on just sucrose or the bitter meal, the team determined how much they preferred one or the other.

Intestinal tumors did not alter the flies' rejection of three of these aversive compounds, but did change their taste preference for ARI. Two of the fly cancer models now showed no preference for sucrose alone; They ate both dishes with the same frequency. The third strain was even more attracted to ARI than to sucrose alone. Specifically, when researchers examined the effects of ARI on tumors, they found that it suppressed cell proliferation. Even consumption for two days resulted in sustained suppression of intestinal tumor growth.

Montell and his colleagues then explored the neural mechanisms behind this change in taste. The tumor could change the way the flies' bitter-sensitive taste receptor neurons respond to ARI, or the change could occur in the brain after this interaction, or both. To test the first hypothesis, the team conducted electrophysiological experiments on the taste sensory cells on the flies' trunks and legs. They found that these peripheral neurons responded no differently to ARI in flies with intestinal tumors than in control flies. Therefore, the change in taste preference likely occurs in the central nervous system, although the details are still unknown.

“[The findings] “suggest that there is something about the cancer that changes the brain so that this connection is no longer aversive,” said Jeremy Borniger, a cancer neuroscientist at Cold Spring Harbor Laboratory who was not involved in the present study. “The next step is to figure out which neurons or which groups of neurons in the brain regulate this process – how does the tumor change these cells so that they receive the same signals from the taste of this compound and then interpret them differently?”

Unfortunately, despite its tumor-suppressing effects, ARI is too toxic to the kidneys and liver to be developed into a drug. However, the study's approach could open up promising avenues for discovering medicinal compounds. For Montell, this is actually the most exciting result of this work: it is becoming established Drosophila as an animal model for self-medication and thus as a system for screening thousands of molecules for potential novel drugs against gastrointestinal cancer. “The first screen would look for chemicals for which [gut tumor-bearing flies] have an increased preference. . .and then which ones you find actually extend their lifespan,” he explained. While scientists have used fruit flies to screen cancer drugs before, Montell noted, “Conceptually, this would be different because self-medication would be used as the primary screen, so people have never done that before.”⁴