Imatinib inhibits proliferation of Ewing tumor cells mediated by the stem cell factor/KIT receptor pathway, and sensitizes cells to vincristine and doxorubicin-induced apoptosis
Iranzu González (1), Enrique J. Andréu [SP] (2), Ángel Panizo (3), Susana Inogés [SP] (2), Ana Fontalba (6), José Luis Fernández-Luna (6), Mirella Gaboli (4), Luis Sierrasesúmaga (4), Salvador Martín-Algarra (5), Javier Pardo [SP] (3), Felipe Prósper (2) and Enrique de Álava (7)
(1) Department of Histology and Pathology, School of Medicine- Universidad de Navarra, Pamplona, Spain.
(2) Area of Cell Therapy, Clínica Universitaria de Navarra-Universidad de Navarra, Pamplona, Spain.
(3) Department of Pathology, Clínica Universitaria de Navarra-Universidad de Navarra, Pamplona, Spain.
(4) Department of Pediatrics, Clínica Universitaria de Navarra-Universidad de Navarra, Pamplona, Spain.
(5) Department of Oncology, Clínica Universitaria de Navarra-Universidad de Navarra, Pamplona, Spain.
(6) Molecular Genetics Unit, Hospital Universitario Marqués de Valdecilla, Escuela de Enfermería, Santander, Spain.
(7) Laboratory 20-Molecular Pathology, Centro de Investigación del Cáncer, Universidad de Salamanca-CSIC, Campus Miguel de Unamuno s/n, Salamanca, Spain
Magazine: Clinical Cancer Research
Date: Jan 1, 2004Cell Therapy Area [SP] Pediatrics [SP] Pathological Anatomy [SP]
PURPOSE AND EXPERIMENTAL DESIGN
The stem cell factor/KIT receptor loop may represent a novel target for molecular-based therapies of Ewing tumor. We analyzed the in vitro impact of KIT blockade by imatinib in Ewing tumor cell lines.
KIT expression was detected in 4 of 4 Ewing tumor cell lines and in 49 of 110 patient samples (44.5%) by immunohistochemistry and/or Western blot analysis. KIT expression was stronger in Ewing tumors showing EWS-FLI1 nontype 1 fusions. Despite absence of c-kit mutations, constitutive and ligand-inducible phosphorylation of KIT was found in all tumor cell lines, indicating an active receptor. Treatment with KIT tyrosine kinase inhibitor imatinib (0.5-20 micro M) induced down-regulation of KIT phosphorylation and dose response inhibition of cell proliferation (IC(50), 12-15 micro M). However, imatinib administered alone at doses close to IC(50) for growth inhibition (10 micro M) did not induce a significant increase in apoptosis. We then analyzed if blockade of KIT loop through imatinib (10 micro M) was able to increase the antitumor in vitro effect of doxorubicin (DXR) and vincristine (VCR), drugs usually used in Ewing tumor treatment. Addition of imatinib decreased in 15-20 and 15-36% of the proliferative rate of Ewing tumor cells exposed to DXR and VCR, respectively, and increased in 15 and 30% of the apoptotic rate of Ewing tumor cells exposed to the same drugs.
Inhibition of Ewing tumor cell proliferation by imatinib is mediated through blockade of KIT receptor signaling. Inhibition of KIT increases sensitivity of these cells to DXR and VCR. This study supports a potential role for imatinib in the treatment of Ewing tumor.
CITATION Clin Cancer Res. 2004 Jan 15;10(2):751-61
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