title: Targeting the p38 MAPK pathway inhibits irinotecan resistance in colon adenocarcinoma.
abstract: Despite recent advances in the treatment of colon cancer, tumor resistance is a frequent cause of chemotherapy failure. To better elucidate the molecular mechanisms involved in resistance to irinotecan (and its active metabolite SN38), we established SN38-resistant clones derived from HCT-116 and SW48 cell lines. These clones show various levels (6- to 60-fold) of resistance to SN-38 and display enhanced levels of activated MAPK p38 as compared with the corresponding parental cells. Because four different isoforms of p38 have been described, we then studied the effect of p38 overexpression or downregulation of each isoform on cell sensivity to SN38 and found that both α and β isoforms are involved in the development of resistance to SN38. In this line, we show that cell treatment with SB202190, which inhibits p38α and p38β, enhanced the cytotoxic activity of SN38. Moreover, p38 inhibition sensitized tumor cells derived from both SN38-sensitive and -resistant HCT116 cells to irinotecan treatment in xenograft models. Finally, we detected less phosphorylated p38 in primary colon cancer of patients sensitive to irinotecan-based treatment, compared with nonresponder patients. This indicates that enhanced level of phosphorylated p38 could predict the absence of clinical response to irinotecan. Altogether, our results show that the p38 MAPK pathway is involved in irinotecan sensitivity and suggest that phosphorylated p38 expression level could be used as a marker of clinical resistance to irinotecan. They further suggest that targeting the p38 pathway may be a potential strategy to overcome resistance to irinotecan-based chemotherapies in colorectal cancer.
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM, U896, Montpellier, F-34298 France.
authors.forename: Salomé
authors.initials: S
authors.lastname: Paillas
authors.forename: Florence
authors.initials: F
authors.lastname: Boissière
authors.forename: Fréderic
authors.initials: F
authors.lastname: Bibeau
authors.forename: Amélie
authors.initials: A
authors.lastname: Denouel
authors.forename: Caroline
authors.initials: C
authors.lastname: Mollevi
authors.forename: Annick
authors.initials: A
authors.lastname: Causse
authors.forename: Vincent
authors.initials: V
authors.lastname: Denis
authors.forename: Nadia
authors.initials: N
authors.lastname: Vezzio-Vié
authors.forename: Laetitia
authors.initials: L
authors.lastname: Marzi
authors.forename: Cédric
authors.initials: C
authors.lastname: Cortijo
authors.forename: Imade
authors.initials: I
authors.lastname: Ait-Arsa
authors.forename: Nadav
authors.initials: N
authors.lastname: Askari
authors.forename: Philippe
authors.initials: P
authors.lastname: Pourquier
authors.forename: Pierre
authors.initials: P
authors.lastname: Martineau
authors.forename: Maguy
authors.initials: M
authors.lastname: Del Rio
authors.forename: Céline
authors.initials: C
authors.lastname: Gongora
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D045325:HCT116 Cells; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D007150:Immunohistochemistry; D000077146:Irinotecan; D007527:Isoenzymes; D002955:Leucovorin / Q000008:administration & dosage; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D007093:Imidazoles; D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D000077146:Irinotecan; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin