Predictability, efficacy and safety of radiosensitization of glioblastoma-initiating cells by the ATM inhibitor KU-60019.
We have previously shown that pharmacological inhibition of ataxia telangiectasia mutated (ATM) protein sensitizes glioblastoma-initiating cells (GICs) to ionizing radiation (IR). Herein, we report the experimental conditions to overcome GIC radioresistance in vitro using the specific ATM inhibitor KU-60019, two major determinants of the tumor response to this drug and the absence of toxicity of this treatment in vitro and in vivo. Repeated treatments with KU-60019 followed by IR substantially delayed GIC proliferation in vitro and even eradicated radioresistant cells, whereas GIC treated with vehicle plus radiation recovered early and expanded. The tumor response to the drug occurred under a cutoff level of expression of TP53 and over a cutoff level of expression of phosphatidylinositol 3-kinase (PI3K). No increased clastogenicity or point mutagenicity was induced by KU-60019 plus radiation when compared to vehicle plus radiation. No significant histological changes to the brain or other organs were observed after prolonged infusion into the brain of KU-60019 at millimolar concentrations. Taken together, these findings suggest that GIC-driven tumors with low expression of TP53 and high expression of PI3K might be effectively and safely radiosensitized by KU-60019.
Mutagenesis Unit, IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Donatella
D
Vecchio
Antonio
A
Daga
Elisa
E
Carra
Daniela
D
Marubbi
Gabriella
G
Baio
Carlo E
CE
Neumaier
Stefano
S
Vagge
Renzo
R
Corvò
Maria
M
Pia Brisigotti
Jean
J
Louis Ravetti
Annalisa
A
Zunino
Alessandro
A
Poggi
Samantha
S
Mascelli
Alessandro
A
Raso
Guido
G
Frosina
D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D051379:Mice; D009025:Morpholines / Q000494:pharmacology*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013892:Thioxanthenes / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
C546193:2-(2,6-dimethylmorpholin-4-yl)-N-(5-(6-morpholin-4-yl-4-oxo-4H-pyran-2-yl)-9H-thioxanthen-2-yl)acetamide; D009025:Morpholines; D011838:Radiation-Sensitizing Agents; D013892:Thioxanthenes
DNA damage response; PI3K; TP53; glioblastoma; radiotherapy; resistance