title: Dual inhibition of COX-2/5-LOX blocks colon cancer proliferation, migration and invasion in vitro.
abstract: Inflammation is emerging as a new hallmark of cancer. Arachidonic acid (AA) metabolism, the family of cyclooxygenases (COXs) and lipoxygenase (LOX) play important roles in AA-related inflammatory cascades. In 94 colorectal cancer samples collected from the Han population, the immunohistochemical results indicated that 68% of the patients with colorectal cancer had a co-expression of both COX-2 and 5-LOX, while both displayed low expression in the matched normal tissues. In cell lines, three colorectal cancer cell lines exhibited high expression of COX-2 and 5-LOX. During stable silencing of the expression of COX-2 or 5-LOX in LoVo cancer cells, we found that downregulation of either COX-2 or 5-LOX significantly diminished the growth, migration and invasion of the colon cancer cells and specifically, downregulation of COX-2 could elicit upregulation of 5-LOX protein and vice versa. The above results suggested that the simultaneous blocking of COX-2 and 5-LOX activity may bring more potential benefits in managing the progression of colon cancer. Therefore, we sought to explore the effectiveness of a dual COX-2/5-LOX inhibitor darbufelone on the proliferation, migration, invasion and apoptosis of colon cancer cells, as well as the underlying mechanism of action. The results indicated that darbufelone significantly decreased the proliferative and invasive abilities of the colon cancer cells, in a dose-dependent manner. During the study of the related mechanisms, we found an upregulation of p27 and downregulation of cyclin D1 as well as CDK4 after darbufelone treatment, which indicated that darbufelone could arrest the cell cycle of LoVo cells at the G0/G1 phase. Furthermore, the activation of caspase-3 and -9, upregulation of Bax and downregulation of Bcl-2 demonstrated the occurrence of apoptosis by darbufelone. Finally, darbufelone also prevented the migration and invasion of LoVo cells, which may be ascribed to the upregulation of E-cadherin and ZO-1. In summary, our data suggest that the inhibition of both COX-2/5-LOX may be an effective therapeutic approach for colon cancer management, particularly for those patients with high expression of COX-2/5-LOX.
authors.affiliation: Department of Drugs and Pharmacology, Ningbo Institute of Medical Sciences, Ningbo, Zhejiang 315020, P.R. China.
authors.forename: Xiao-Hang
authors.initials: XH
authors.lastname: Che
authors.affiliation: College of Chemistry and Bio-Engineering, Yichun University, Yichun, Jiangxi 336000, P.R. China.
authors.forename: Chun-Lin
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Department of Drugs and Pharmacology, Ningbo Institute of Medical Sciences, Ningbo, Zhejiang 315020, P.R. China.
authors.forename: Xiao-Lei
authors.initials: XL
authors.lastname: Ye
authors.affiliation: Department of Urology, Ningbo Urinary Kidney Disease Hospital, Ningbo, Zhejiang 315100, P.R. China.
authors.forename: Guo-Bin
authors.initials: GB
authors.lastname: Weng
authors.affiliation: Department of Medical Oncology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, P.R. China.
authors.forename: Xian-Zhi
authors.initials: XZ
authors.lastname: Guo
authors.affiliation: Ningbo Clinical and Pathology Diagnostic Center, Ningbo, Zhejiang 315021, P.R. China.
authors.forename: Wen-Ying
authors.initials: WY
authors.lastname: Yu
authors.affiliation: Department of Drugs and Pharmacology, Ningbo Institute of Medical Sciences, Ningbo, Zhejiang 315020, P.R. China.
authors.forename: Jin
authors.initials: J
authors.lastname: Tao
authors.affiliation: Department of Drugs and Pharmacology, Ningbo Institute of Medical Sciences, Ningbo, Zhejiang 315020, P.R. China.
authors.forename: Yi-Chen
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Department of Drugs and Pharmacology, Ningbo Institute of Medical Sciences, Ningbo, Zhejiang 315020, P.R. China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Chen
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001094:Arachidonate 5-Lipoxygenase / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis; D053778:Thiazolidines / Q000008:administration & dosage*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D009363:Neoplasm Proteins; D053778:Thiazolidines; C109268:darbufelone; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C583212:ALOX5 protein, human