title: Inhibition of the p38 MAPK pathway sensitises human colon cancer cells to 5-fluorouracil treatment.
abstract: Colorectal cancer is the third most common cause of cancer-related deaths in the Western world. 5-Fluorouracil (5-FU) based chemotherapeutic regimes have been the mainstay of systemic treatment for disseminated colorectal cancer for many years. However, it only produces a 25% response rate due to the drug-resistance. The mitogen-activated protein kinase (MAPK) pathway is involved in the anti-apoptotic process; its activation provides cancer cells with a survival advantage to escape the apoptotic challenge. This study assessed whether the p38 MAPK pathway is involved in 5-FU resistance in colorectal cancer cells. 5-FU only or 5-FU combined with a p38 MAPK pathway inhibitor (SB203580) was used to treat 5-FU-resistant colorectal cancer cells. The effect of the treatment on cell viability, death and caspase activities was assessed. Western blotting was used to investigate the responses of apoptosis-related proteins following the treatment. Results showed that p38 MAPK inhibitor significantly increased colorectal cancer cell sensitivity to 5-FU. SB203580 in combination with 5-FU significantly reduced cell viability (P<0.01), and increased cell death and cellular caspase activity (P<0.01). Western blotting data revealed that SB203580 sensitises cancer cells to 5-FU due to an increase in Bax expression. These findings suggest that p38 MAPK is involved in cancer cell survival, and that the inhibition of p38 MAPK can enhance 5-FU to kill colorectal cancer cells.
authors.affiliation: Division of Surgery and Interventional Science, UCL Medical School, University College London, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK. shiyu.yang@medsch.ucl.ac.uk
authors.forename: Shi Yu
authors.initials: SY
authors.lastname: Yang
authors.forename: Anur
authors.initials: A
authors.lastname: Miah
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Sales
authors.forename: Barry
authors.initials: B
authors.lastname: Fuller
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Seifalian
authors.forename: Marc
authors.initials: M
authors.lastname: Winslet
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005472:Fluorouracil / Q000494:pharmacology*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000964:Antimetabolites, Antineoplastic; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases; D005472:Fluorouracil