title: The selective Aurora-A kinase inhibitor MLN8237 (alisertib) potently inhibits proliferation of glioblastoma neurosphere tumor stem-like cells and potentiates the effects of temozolomide and ionizing radiation.
abstract: The selective Aurora-A kinase inhibitor MLN8237 is in clinical trials for hematologic malignancies, ovarian cancer and other solid tumors. We previously showed that MLN8237 is potently antiproliferative toward standard monolayer-cultured glioblastoma cells. We have now investigated the effect of MLN8237 with and without temozolomide or ionizing radiation on the proliferation of glioblastoma tumor stem-like cells (neurospheres) using soft agar colony formation assays and normal human astrocytes by MTT assay. Western blotting was utilized to compare MLN8237 IC50s to cellular Aurora-A and phosphoThr(288)Aurora-A levels. MLN8237 was more potently antiproliferative to neurosphere cells than to standard monolayer glioma cells, and was non-toxic to normal human astrocytes. Western blot analysis revealed that MLN8237 treatment inhibits phosphoThr(288)Aurora-A levels providing proof of drug target-hit in glioblastoma cells. Furthermore, phosphoThr(288)Aurora-A levels partially predicted the antiproliferative efficacy of MLN8237. We also found that Aurora-A inhibition by MLN8237 was synergistic with temozolomide and potentiated the effects of ionizing radiation on colony formation in neurosphere glioblastoma tumor stem-like cells. These results further support the potential of Aurora-A inhibitors as primary chemotherapy agents or biologic response modifiers in glioblastoma patients.
authors.affiliation: Department of Neurosurgery, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Hong
authors.forename: James P
authors.initials: JP
authors.lastname: O'Donnell
authors.forename: Clarence R
authors.initials: CR
authors.lastname: Salazar
authors.forename: James R
authors.initials: JR
authors.lastname: Van Brocklyn
authors.forename: Kahlil D
authors.initials: KD
authors.lastname: Barnett
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Pearl
authors.forename: Ana C
authors.initials: AC
authors.lastname: deCarvalho
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Ecsedy
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Brown
authors.forename: Tom
authors.initials: T
authors.lastname: Mikkelsen
authors.forename: Norman L
authors.initials: NL
authors.lastname: Lehman
mesh_terms: D017209:Apoptosis; D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D049109:Cell Proliferation; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011839:Radiation, Ionizing; D000077204:Temozolomide
chemical_list: D001381:Azepines; C550258:MLN 8237; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D003606:Dacarbazine; D000077204:Temozolomide