title: CPT-11 activates NLRP3 inflammasome through JNK and NF-κB signalings.
abstract: CPT-11 is widely used for cancer therapy as a chemotherapeutic agent. Despite its good efficacy, a large number of side effects appeared during decades of clinical application. Delayed diarrhea, at dose limiting toxicity, happens after 24h of treatment and the rate of occurrence is up to 90%. Although many investments have been made on this negative impact, the real molecular mechanism of delayed diarrhea is poorly understood. In this study, we have discovered that CPT-11 promotes macrophage infiltration into intestinal tissues and activates the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome, resulting in a robust IL-1β response and colonic inflammation similar to DSS (dextran sodium sulfate) induced experimental colitis. CPT-11 plus LPS primed mouse bone marrow-derived macrophages (BMDMs) and human acute monocytic leukemia cells (THP-1 cells) staying in a highly activated status, showing increased caspase-1 activity and releasing great amounts of IL-1β and IL-18 as detected by ELISA and western blot. A further mechanism showed that JNK and NF-κB signaling pathways participated in inflammatory responses activated by CPT-11. These results prompted us to suggest that the NLRP3-IL-1β signaling pathway might play an important role in CPT11-induced colitis. Our findings provide a basis for developing novel strategies that improve clinical implications of CPT-11.
authors.affiliation: Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, 300, Guangzhou Road, Nanjing 210029, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210046, China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, 300, Guangzhou Road, Nanjing 210029, China.
authors.forename: Weicheng
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, 300, Guangzhou Road, Nanjing 210029, China.
authors.forename: LeLe
authors.initials: L
authors.lastname: Li
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210046, China. Electronic address: molpharm@163.com.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210046, China. Electronic address: xudongwu@nju.edu.cn.
authors.forename: Xudong
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, 300, Guangzhou Road, Nanjing 210029, China. Electronic address: guluer@163.com.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Gu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000633:toxicity; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D045744:Cell Line, Tumor; D003092:Colitis / Q000139:chemically induced* / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D003106:Colon / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D003967:Diarrhea / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D000077146:Irinotecan; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010539:Permeability; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D059004:Topoisomerase I Inhibitors / Q000633:toxicity*
chemical_list: D000893:Anti-Inflammatory Agents; C508606:CXCL8 protein, human; D002352:Carrier Proteins; C508585:IL1B protein, human; C587672:IL1B protein, mouse; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D016209:Interleukin-8; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D047428:Protein Kinase Inhibitors; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D048031:JNK Mitogen-Activated Protein Kinases; D020170:Caspase 1; D002166:Camptothecin
keywords: CPT-11; Delayed diarrhea; Experimental colitis; JNK; NF-κB; NLRP3 inflammasome