title: Imatinib mesylate radiosensitizes human glioblastoma cells through inhibition of platelet-derived growth factor receptor.
abstract: Imatinib mesylate is a small molecule inhibitor of the c-Abl, platelet-derived growth factor (PDGF) receptor and c-Kit tyrosine kinases that is approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML) and gastrointestinal stromal tumors. Glioblastoma multiforme is a highly malignant primary brain tumor that is usually treated with surgery and/or radiotherapy. Previous studies implicate an autocrine loop caused by high expression of PDGF and its receptor, PDGFR, in the proliferation of some glioblastomas. Here, we demonstrate that pretreatment of a human glioblastoma cell line, RuSi RS1, with imatinib significantly enhanced the cytotoxic effect of ionizing radiation. This effect was not seen in human breast cancer (BT20) and colon cancer (WiDr) cell lines. Whereas c-Abl and c-Kit were expressed about equally in the three cell lines, RuSi RS1 cells showed significantly higher expression of PDGFR-beta protein in comparison to BT20 and WiDr. Imatinib treatment of RuSi RS1 cells decreased overall levels of cellular tyrosine phosphorylation and specifically inhibited phosphorylation of PDGFR-beta, while c-Abl was not prominently activated in these cells. These results suggest that imatinib may have clinical utility as a radiosensitizer in the treatment of human glioblastoma, possibly through disruption of an autocrine PDGF/PDGFR loop.
authors.affiliation: Medizinische Klinik für Hämatologie und Onkologie, Campus Virchow, Charité, Humboldt Universität, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Holdhoff
authors.forename: Karl-Anton
authors.initials: KA
authors.lastname: Kreuzer
authors.forename: Christine
authors.initials: C
authors.lastname: Appelt
authors.forename: Regina
authors.initials: R
authors.lastname: Scholz
authors.forename: Il-Kang
authors.initials: IK
authors.lastname: Na
authors.forename: Bert
authors.initials: B
authors.lastname: Hildebrandt
authors.forename: Hanno
authors.initials: H
authors.lastname: Riess
authors.forename: Andreas
authors.initials: A
authors.lastname: Jordan
authors.forename: Christian A
authors.initials: CA
authors.lastname: Schmidt
authors.forename: Richard A
authors.initials: RA
authors.lastname: Van Etten
authors.forename: Bernd
authors.initials: B
authors.lastname: Dörken
authors.forename: Philipp
authors.initials: P
authors.lastname: le Coutre
mesh_terms: D001549:Benzamides; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects; D003110:Colonic Neoplasms; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005909:Glioblastoma; D006801:Humans; D000068877:Imatinib Mesylate; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D011838:Radiation-Sensitizing Agents; D000068877:Imatinib Mesylate; D017479:Receptors, Platelet-Derived Growth Factor