Irinotecan (CPT-11)-induced elevation of bile acids potentiates suppression of IL-10 expression

Journal Article · Fri Jan 15 00:00:00 EST 2016 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2015.12.003· OSTI ID:22687877

Fang, Zhong-Ze ^[1]; Zhang, Dunfang ^[2]; Cao, Yun-Feng ^[3]; Xie, Cen ^[1]; Lu, Dan ^[4]; Sun, Dong-Xue; Tanaka, Naoki; Jiang, Changtao ^[1]; Chen, Qianming; Chen, Yu ^[2]; Wang, Haina ^[5]

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1. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (United States)
2. State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu (China)
3. Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences and First Affiliated Hospital of Liaoning Medical University, Dalian (China)
4. Department of Immunology, Tianjin Key Laboratory of Cellular and Molecular Immunology, Tianjin Medical University, Tianjin (China)
5. School of Pharmaceutical Sciences, Shandong University, Jinan (China)

Irinotecan (CPT-11) is a first-line anti-colon cancer drug, however; CPT-11-induced toxicity remains a key factor limiting its clinical application. To search for clues to the mechanism of CPT-11-induced toxicity, metabolomics was applied using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry. Intraperitoneal injection of 50 mg/kg of CPT-11 induced loss of body weight, and intestine toxicity. Changes in gallbladder morphology suggested alterations in bile acid metabolism, as revealed at the molecular level by analysis of the liver, bile, and ileum metabolomes between the vehicle-treated control group and the CPT-11-treated group. Analysis of immune cell populations further showed that CPT-11 treatment significantly decreased the IL-10-producing CD4 T cell frequency in intestinal lamina propria lymphocytes, but not in spleen or mesenteric lymph nodes. In vitro cell culture studies showed that the addition of bile acids deoxycholic acid and taurodeoxycholic acid accelerated the CPT-11-induced suppression of IL-10 secretion by activated CD4{sup +} naive T cells isolated from mouse splenocytes. These results showed that CPT-11 treatment caused metabolic changes in the composition of bile acids that altered CPT-11-induced suppression of IL-10 expression. - Highlights: • CPT-11 is an effective anticancer drug, but induced toxicity limits its application in the clinic. • CPT-11 decreased IL-10-producing CD4 T cell frequency in intestinal lamina propria lymphocytes. • CPT-11 altered the composition of bile acid metabolites, notably DCA and TDCA in liver, bile and intestine. • DCA and TDCA potentiated CPT-11-induced suppression of IL-10 secretion by active CD4{sup +} naive T cells.

• OSTI ID: 22687877
• Journal Information: Toxicology and Applied Pharmacology, Vol. 291; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANTINEOPLASTIC DRUGS
BILE
BILIARY TRACT
CELL CULTURES
CHOLIC ACID
IN VITRO
INHIBITION
INTRAPERITONEAL INJECTION
IONIZATION
LARGE INTESTINE
LIQUID COLUMN CHROMATOGRAPHY
LIVER
LYMPH
LYMPH NODES
LYMPHOCYTES
LYMPHOKINES
MASS SPECTROSCOPY
MICE
NEOPLASMS
QUADRUPOLES
RECEPTORS
SMALL INTESTINE
SPLEEN
TIME-OF-FLIGHT METHOD
TOXICITY