Targeting the p38 MAPK pathway inhibits irinotecan resistance in colon adenocarcinoma. - Inserm - Institut national de la santé et de la recherche médicale Accéder directement au contenu
Article Dans Une Revue Cancer Research Année : 2011

Targeting the p38 MAPK pathway inhibits irinotecan resistance in colon adenocarcinoma.

Caroline Mollevi

Résumé

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.
Fichier principal
Vignette du fichier
inserm-00555572_edited.pdf (481.01 Ko) Télécharger le fichier
18-11-2010-PaillasEtAl.pdf (207.53 Ko) Télécharger le fichier
figures_8.ppt (6.58 Mo) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)
Origine : Fichiers produits par l'(les) auteur(s)
Format : Autre
Loading...

Dates et versions

inserm-00555572 , version 1 (21-12-2011)

Identifiants

Citer

Salomé Paillas, Florence Boissière, Frédéric Bibeau, Amélie Denouel, Caroline Mollevi, et al.. Targeting the p38 MAPK pathway inhibits irinotecan resistance in colon adenocarcinoma.: Activated p38 and chemoresistance. Cancer Research, 2011, 71 (3), pp.1041-9. ⟨10.1158/0008-5472.CAN-10-2726⟩. ⟨inserm-00555572⟩
319 Consultations
798 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More