A study by researchers at Northwest A&F University in China has found that the anti-tumor drug, camptothecin (CPT) promotes weight loss in mice at low doses by activating a natural hunger-suppressing pathway. The study, headed by Jiang Wei Wu, PhD, could point to a therapeutic strategy for obesity through the induction of growth differentiation factor 15 (GDF15).
“We believe our results convincingly argue that camptothecin may have therapeutic benefits for obesity and its associated metabolic disorders,” Wu said. “Further study is needed to evaluate its efficacy and safety in advanced models to increase the translational impact.” Interestingly, Wu and colleagues noted in their published paper in PLOS Biology (“Camptothecin effectively treats obesity in mice through GDF15 induction”) GDF15 is also implicated in life span, atherosclerotic cardiovascular disease, inflammation and immunology, mitochondrial disease, cancer, rheumatoid arthritis, chronic renal, and cardiac failure. “Therefore, our findings open avenues of CPT research in these fields,” concluded Wu, together with co-authors Rui Xin Zhang PhD, and Bo Xia, PhD.
Obesity is a global health problem that predisposes people to diseases such as type 2 diabetes, cardiovascular diseases, fatty liver, and even cancer, the authors wrote. While there are some FDA-approved drug-based treatments for obesity, “the problem has not been well resolved because many targets have limitations and functions only for a small population,” while for some FDA-approved weight-control medications there have been repeated reports of side effects such as gastrointestinal disorders and myopathy. “Therefore, exploring new therapeutic targets and understanding their regulations for drug development are current areas of intense interest and active investigation.”
GDF15 has emerged as a new anti-obesity target, the investigators noted. The stress-responsive cytokine is expressed in a variety of tissues and is secreted into the circulation in response to stimuli, as part of a range of disease processes. Previous work has shown that increasing GDF15 leads to a drop in body weight, while its suppression leads to obesity. “Elevating GDF15 levels by transgenic overexpression or pharmacological administration in mice and nonhuman primates leads to a marked fall in body weight,” the team explained. “Mice lacking GDF15 become more obese on a high-fat diet than wild-type (WT) controls.”
To search for drugs that could increase GDF15 production, the authors turned to the “Connectivity Map” (CMAP), a database of gene expression profiles of human cells in response to drug exposure. They found that cells exposed to camptothecin increased their expression of GDF15. Camptothecin—a compound derived from the Asian tree Camptotheca acuminate—is a known inhibitor of a DNA repair enzyme. But while camptothecin has been investigated in Phase II trials against advanced gastrointestinal adenocarcinoma, at the dose level and frequency tested, treatment resulted in side effects that hampered its initial clinical development as a chemotherapeutic, the authors pointed out.
The newly reported study aimed to determine the potential link between CPT and changes in circulating GDF15 levels, food intake, and body weight. In tests in both high-fat diet (HFD) diet-induced obese (DIO) mice, and in genetically obese, leptin-deficient ob/ob mice, the authors showed that oral administration of camptothecin at 1 mg/kg body weight rapidly elevated the level of GDF15 in the blood, and over the course of 30 days, reduced food intake by about 12% and body weight by about 11%.
“1 mg kg−1 of CPT administration resulted in a 2.2- and 2.0-fold increase in circulating GDF15 levels after 1 h in DIO mice and ob/ob mice, respectively,” they wrote. In contrast, camptothecin did not elevate GDF15 a, in lean mice, and there was no effect on either food intake or body weight.
DOI and ob/ob mice then treated for 30 days using camptothecin at a dose of 1 mg/kg body weight per day also demonstrated significantly increased circulating GDF15 levels. The treated animals exhibited reduced food intake, and reduced body weight. Weight loss was largely due to reductions in fat mass. Again, lean mice given camptothecin for 30 days did not show any increase in GDF15 levels, and their food intake and body weight also remained similar to that of control animals.
“CPT-induced GDF15 elevations were shown in obese mice, but not in lean mice,” the team noted. “Thus, the mechanism underlying the obesity-dependent effect of CPT is highly probably due to serum levels of GDF15, which is relatively low and not sufficient to suppress food intake and body weight in lean mice.”
Tests indicated that the liver was the primary source of circulating GDF15 following CPT treatment, while further investigation found that CPT treatment of obese animals had the added benefits of reducing hyperlipidemia, fatty liver, and hyperglycemia. The metabolic benefits of CPT on glucose homeostasis were revealed by a glucose tolerance test (GTT) and an insulin tolerance test (ITT). “Collectively, these results demonstrate that CPT ameliorates obesity, thereby reducing hyperlipidemia, fatty liver, and hyperglycemia in obese mice,” the investigators stated.
Experiments confirmed that the effects of camptothecin were specific to GDF15, and that GDF15 exerted its effect through its receptor, GFRAL. An antibody against GDF15 prevented weight loss in obese animals, as did knocking down GFRAL expression. “We provide a mechanistic basis underlying the metabolic benefits of CPT. Using GDF15 neutralization or its receptor GFRAL deficiency in mice, we corroborated that GDF15-GFRAL signaling is indispensable for the metabolic actions of CPT,” the team commented.
While the safety of camptothecin as an anti-obesity drug has yet to be determined, Wu noted that the dose used in the reported study, if scaled up to a human, would be about one-thirtieth of the lowest dose used in human anticancer trials. Additionally, the anti-obesity mechanism appears to be separate from the anticancer mechanism—which involves blocking the function of the DNA-repair enzyme topoisomerase—and to function at a much lower drug concentration.
“This work reveals important physiological effects of CPT that could provide therapeutic benefits for obesity,” the team concluded. “Our strategy from virtual screening to validation, and from animal physiology to mechanistic elucidation, represents an illustrative approach potentially valuable for the next generation of translational medicine.”
Wu added, “In this study, by using in silico drug-screening approach, we discovered that CPT, a previously identified anti-tumor drug by the U.S. National Cancer Institute, is a GDF15 inducer. CPT elevates circulating GDF15 via activation of hepatic ISR [integrated stress response] pathway, this activates the GDF15 receptor GFRAL in the hindbrain AP, which subsequently suppresses food intake and reduces body weight in obese mice.”
Interestingly, the investigators noted in their paper, some platinum-based anticancer drugs, such as cisplatin and bleomycin have also been shown to induce GDF15 in subjects with testicular cancer and “one may deduce that a large number of the anticancer drugs could induce GDF15,” they suggested. However, the team pointed out, reported studies have shown that other clinically approved anticancer drugs were unable to induce GDF15. “Therefore, induction of GDF15 by anticancer drugs seems not category-based, but individually different.”
They further concluded, “In summary, CPT ameliorates obesity by acting as a GDF15 inducer, providing a convincing argument that CPT may have therapeutic benefits for obesity and its associated metabolic disorders. Further study is needed to evaluate the efficacy and safety of CPT in advanced models to increase the translational impact.”
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