Anti-cancer drug isolated from Asian tree promotes weight loss in obese mice

Discovered in 1966, the drug camptothecin comes from the Camptotheca tree native to China. The compound’s ability to inhibit a DNA repair enzyme makes it a cytotoxic agent with cancer-killing effects. Now, a group of Chinese scientists has found the drug also has the potential to tackle obesity.

By increasing blood levels of a hunger-suppressing protein, growth differentiation factor 15 (GDF15), camptothecin showed it could lower food intake and reduce body weight in obese mice, researchers at China’s Northwest A&F University reported in a study published in the journal PLOS Biology.

Because the weight loss effect required only a small fraction of the camptothecin dose used in cancer studies, the drug could more easily move into a clinical trial in obesity, the researchers said. The findings also offer clues for developing new anti-obesity treatments.

GDF15, working through its receptor GFRAL, recently emerged as an anti-obesity target. Previous studies have shown that over-expression of the hormone can lead to a marked decrease in body weight in mice and monkeys.

In their search for drugs that could induce GDF15 production, the Northwest A&F scientists screened the “Connectivity Map,” a database of gene expression profiles of human cell lines in response to treatment with more than 6,000 small molecules. Camptothecin returned as a hit, whereas its FDA-approved analog, Pfizer’s chemotherapy Camptosar (irinotecan), ranked far below in terms of GDF15 expression.

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In two mouse models of obesity, camptothecin sustained high circulating levels of GDF15, and the animals started eating less. In mice with obesity because of a high-fat diet, the drug cut the animals’ body weight by about 11% after 30 days, while control mice gained about 9%. The magnitude of body weight reduction was smaller, at about 6%, in genetically modified mice with obesity.

In contrast, in lean mice, camptothecin didn’t affect the rodents' food intake or their body weight, and GDF15 levels themselves remained unchanged, the researchers found.

The weight-loss effect of camptothecin in obese mice mainly came from reductions in unhealthy fat mass. What’s more, the drug also markedly reduced blood levels of triglycerides and total cholesterol, as well as liver fat content and liver enzymes—which indicated improved liver health.

Further analysis confirmed that camptothecin suppressed appetite to help control the mice’s body weight without altering energy expenditure.

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Several obesity meds are already available on the market, including Novo Nordisk’s recently approved GLP-1 injection Wegovy. But the search for more treatments is still on. The Novo Nordisk Foundation recently contributed $47.5 million to facilitate a research collaboration between Danish universities and the Broad Institute of MIT and Harvard, with an initial focus on Type 2 diabetes and obesity.

Last year, a research team at the University of Pennsylvania found the cytokine TSLP promotes weight loss in mice by releasing oil from the skin.

Some people may question the translational potential of camptothecin in human beings, as cytotoxic chemotherapies are known for their side effects, and camptothecin was sidelined as an antitumor drug partly because of them.

But the camptothecin dose used for this mouse anti-obesity study is equivalent to just one-thirtieth of the lowest dose tested in cancer patients, the researchers pointed out. And at that anti-obesity dose, the drug didn’t trigger its documented side effects on hemoglobin levels and white blood cell and platelet counts, nor did it cause diarrhea or hair loss. Plus, the drug's weight loss effects did not depend on the DNA breaks that underpin its cancer-fighting properties. 

The findings provide “a convincing argument” that camptothecin may have therapeutic benefits for obesity and its associated metabolic disorders, the researchers wrote in the study. The team hopes to conduct additional studies in other models to evaluate the drug’s safety and efficacy before launching an in-human study.