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IDO1 Is a Therapeutic Target for Pancreatic Cancer–Associated Depression

犬尿氨酸 吲哚胺2,3-双加氧酶 胰腺癌 依西酞普兰 尾部悬挂试验 抗抑郁药 背景(考古学) 心情 内科学 药理学 癌症 行为绝望测验 内分泌学 化学 医学 生物 色氨酸 生物化学 精神科 氨基酸 古生物学 海马体
作者
Jonathan J. Hue,Hallie J. Graor,Mehrdad Zarei,Erryk Katayama,Karen Ji,Omid Hajihassani,Alexander W. Loftus,Ali Vaziri‐Gohar,Jordan M. Winter
出处
期刊:Molecular Cancer Therapeutics [American Association for Cancer Research]
卷期号:21 (12): 1810-1822 被引量:7
标识
DOI:10.1158/1535-7163.mct-22-0055
摘要

Abstract Metabolites of tryptophan degradation are known to alter mood. Their effects have only been superficially examined in the context of pancreatic cancer. Herein, we study the role of indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme important in the conversion of tryptophan to kynurenine, in a murine model of pancreatic cancer–associated depression. Behavioral tests (open field, forced swim, tail suspension, and elevated plus maze) and biochemical assays (LC-MS metabolomics) were used to characterize a depressive-phenotype in tumor-bearing mice (relative to non–tumor-bearing mice). In addition, we determine whether pharmacologic blockade of IDO1 affects mood in tumor-bearing mice. Immunocompetent mice bearing orthotopic pancreatic tumors exhibit depressive-like behavior relative to non–tumor-bearing mice. Pancreatic tumors strongly express IDO1. Consequently, serum kynurenine levels in tumor-bearing mice are elevated relative to non–tumor-bearing mice. Tumor-bearing mice treated with epacadostat, an IDO1 inhibitor, exhibited improved mood relative to mice receiving vehicle. There was a 95% reduction in serum kynurenine levels in mice receiving epacadostat relative to mice treated with vehicle. As confirmatory evidence of on-target activity, tumors of mice treated with epacadostat exhibited a compensatory increase in IDO1 protein levels. Escitalopram, an approved antidepressant, was ineffective at improving mood in tumor-bearing mice as measured by behavioral assays and did not affect kynurenine levels. Neither epacadostat, nor escitalopram, affected overall survival relative to vehicle. Mice with pancreatic cancer exhibit depressive-like behavior. Epacadostat was effective as an antidepressant for pancreatic cancer–associated depression in mice. These data offer a rationale to consider IDO1 inhibition as a therapeutic strategy to mitigate depressive symptoms in patients with pancreatic cancer.
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