Enhancement of radiation sensitivity, delay of proliferative recovery after radiation and abrogation of MAPK (p44/42) signaling by imatinib in glioblastoma cells.
Glioblastomas are intrinsically resistant to conventional radiation therapy. The present study investigated the possibility that the tyrosine kinase inhibitor, imatinib, could enhance radiation sensitivity and influence proliferative recovery after irradiation in glioblastoma cells. Radiosensitivity was evaluated by clonogenic survival; apoptotic cell death was evaluated using flow cytometric analysis; proliferative recovery was monitored based on viable cell number subsequent to radiation-induced growth arrest; activation of p44/42 MAPK was based on phosphorylation of the protein. Glioblastoma cells pretreated with imatinib demonstrated an enhanced sensitivity to radiation. Imatinib also delayed proliferative recovery in irradiated glioblastoma cells. Imatinib promoted suppression of p44/42 MAPK signaling both when added prior to and post-irradiation. Increased sensitivity to radiation and delayed proliferative recovery in irradiated glioblastoma cells exposed to imatinib may be a consequence of the capacity of imatinib to interfere with p44/42 MAPK kinase signaling. Imatinib may prove to have clinical utility as a neoadjuvant and adjuvant in the treatment of glioblastomas that receive radiation therapy.
Quick
Quincy A
QA
Department of Pharmacology and Toxicology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
Gewirtz
David A
DA
D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002469:Cell Separation; D003131:Combined Modality Therapy; D005434:Flow Cytometry; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D006801:Humans; D000068877:Imatinib Mesylate; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D015398:Signal Transduction; D013997:Time Factors
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D011838:Radiation-Sensitizing Agents; D000068877:Imatinib Mesylate; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3