title: Semapimod sensitizes glioblastoma tumors to ionizing radiation by targeting microglia.
abstract: Glioblastoma is the most malignant and lethal form of astrocytoma, with patients having a median survival time of approximately 15 months with current therapeutic modalities. It is therefore important to identify novel therapeutics. There is mounting evidence that microglia (specialized brain-resident macrophages) play a significant role in the development and progression of glioblastoma tumors. In this paper we show that microglia, in addition to stimulating glioblastoma cell invasion, also promote glioblastoma cell proliferation and resistance to ionizing radiation in vitro. We found that semapimod, a drug that selectively interferes with the function of macrophages and microglia, potently inhibits microglia-stimulated GL261 invasion, without affecting serum-stimulated glioblastoma cell invasion. Semapimod also inhibits microglia-stimulated resistance of glioblastoma cells to radiation, but has no significant effect on microglia-stimulated glioblastoma cell proliferation. We also found that intracranially administered semapimod strongly increases the survival of GL261 tumor-bearing animals in combination with radiation, but has no significant benefit in the absence of radiation. In conclusion, our observations indicate that semapimod sensitizes glioblastoma tumors to ionizing radiation by targeting microglia and/or infiltrating macrophages.
authors.affiliation: Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research at North Shore-LIJ, Manhasset, New York, United States of America.
authors.forename: Ian S
authors.initials: IS
authors.lastname: Miller
authors.affiliation: Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research at North Shore-LIJ, Manhasset, New York, United States of America.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Didier
authors.affiliation: Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research at North Shore-LIJ, Manhasset, New York, United States of America.
authors.forename: David W
authors.initials: DW
authors.lastname: Murray
authors.affiliation: Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research at North Shore-LIJ, Manhasset, New York, United States of America.
authors.forename: Tia H
authors.initials: TH
authors.lastname: Turner
authors.affiliation: Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research at North Shore-LIJ, Manhasset, New York, United States of America.
authors.forename: Magimairajan
authors.initials: M
authors.lastname: Issaivanan
authors.affiliation: Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research at North Shore-LIJ, Manhasset, New York, United States of America.
authors.forename: Rosamaria
authors.initials: R
authors.lastname: Ruggieri
authors.affiliation: Center for Molecular Innovation, The Feinstein Institute for Medical Research at North Shore-LIJ, Manhasset, New York, United States of America.
authors.forename: Yousef
authors.initials: Y
authors.lastname: Al-Abed
authors.affiliation: Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research at North Shore-LIJ, Manhasset, New York, United States of America.
authors.forename: Marc
authors.initials: M
authors.lastname: Symons
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D059248:Chemoradiotherapy; D005909:Glioblastoma / Q000473:pathology / Q000628:therapy*; D006835:Hydrazones / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects*; D009361:Neoplasm Invasiveness; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D016019:Survival Analysis; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects; D000813:Anilides; D006146:Guanidines
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D006835:Hydrazones; D011838:Radiation-Sensitizing Agents; C097256:semapimod; D000813:Anilides; D006146:Guanidines