title: Free radical derivatives formed from cyclooxygenase-catalyzed dihomo-γ-linolenic acid peroxidation can attenuate colon cancer cell growth and enhance 5-fluorouracil's cytotoxicity.
abstract: Dihomo-γ-linolenic acid (DGLA) and its downstream fatty acid arachidonic acid (AA) are both nutritionally important ω-6 polyunsaturated fatty acids (ω-6s). Evidence shows that, via COX-mediated peroxidation, DGLA and its metabolites (1-series prostaglandins) are associated with anti-tumor activity, while AA and its metabolites (2-series prostaglandins) could be tightly implicated in various cancer diseases. However, it still remains a mystery why DGLA and AA possess contrasting bioactivities. Our previous studies showed that DGLA could go through an exclusive C-8 oxygenation pathway during COX-catalyzed lipid peroxidation in addition to a C-15 oxygenation pathway shared by both DGLA and AA, and that the exclusive C-8 oxygenation could lead to the production of distinct DGLA׳s free radical derivatives that may be correlated with DGLA׳s anti-proliferation activity. In the present work, we further investigate the anti-cancer effect of DGLA׳s free radical derivatives and their associated molecular mechanisms. Our study shows that the exclusive DGLA׳s free radical derivatives from C-8 oxygenation lead to cell growth inhibition, cell cycle arrest and apoptosis in the human colon cancer cell line HCA-7 colony 29, probably by up-regulating the cancer suppressor p53 and the cell cycle inhibitor p27. In addition, these exclusive radical derivatives were also able to enhance the efficacy of 5-Fluorouracil (5-FU), a widely used chemo-drug for colon cancer. For the first time, we show how DGLA׳s radical pathway and metabolites are associated with DGLA׳s anti-cancer activities and able to sensitize colon cancer cells to chemo-drugs such as 5-FU. Our findings could be used to guide future development of a combined chemotherapy and dietary care strategy for colon cancer treatment.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Nursing and Allied Sciences, North Dakota State University, Fargo, ND 58108, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Nursing and Allied Sciences, North Dakota State University, Fargo, ND 58108, USA ; Department of Complex Prescription of TCM, China Pharmaceutical University, Nanjing, Jiangsu 211198, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Qi
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Nursing and Allied Sciences, North Dakota State University, Fargo, ND 58108, USA.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Nursing and Allied Sciences, North Dakota State University, Fargo, ND 58108, USA.
authors.forename: Erxi
authors.initials: E
authors.lastname: Wu
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Nursing and Allied Sciences, North Dakota State University, Fargo, ND 58108, USA.
authors.forename: Steven Y
authors.initials: SY
authors.lastname: Qian
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000737:chemistry / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D055162:Biocatalysis; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005472:Fluorouracil / Q000494:pharmacology*; D005609:Free Radicals / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D015227:Lipid Peroxidation; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D005609:Free Radicals; D011451:Prostaglandin-Endoperoxide Synthases; D015126:8,11,14-Eicosatrienoic Acid; D005472:Fluorouracil
keywords: 5-FU, 5-Fluorouracil; 5-Fluorouracil; 8-HOA, 8-hydroxyoctanoic acid; AA, arachidonic acid; ACN, acetonitrile; COX, cyclooxygenase; COX-catalyzed PUFA peroxidation; Cell cycle and apoptosis; Colon cancer cell line HCA-7 colony 29; D5D, delta-5 desaturase; DGLA, dihomo-γ-linoleic acid; DGLA׳s free radical derivatives; DHA, docosahexaenoic acid; EIC, extracted ion chromatogram; EPA, eicosapentaenoic acid; ESR, electron spin resonance; GC, gas chromatography; HEX, 1-hexanol; HOAc, glacial acetic acid; HPLC/LC, high performance liquid chromatography; HTA, heptanoic acid; LC/MS and ESR spin trapping; MS, mass spectrometry; PGs, prostaglandins; PI, propidium iodide; POBN, α-[4-pyridyl-1-oxide]-N-tert-butyl nitrone; PUFA, polyunsaturated fatty acid; SPE, solid phase extraction; TBS, Tris buffered saline; TIC, total ion chromatogram
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