title: Combined action of the dinuclear platinum compound BBR3610 with the PI3-K inhibitor PX-866 in glioblastoma.
abstract: Polynuclear platinum compounds are more effective at killing glioblastoma cells than cisplatin, work by a different mechanism, and typically do not induce high levels of apoptosis at early time points after exposure. Here, we tested the hypothesis that combining BBR3610, the most potent polynuclear platinum, with a phosphoinositide-3-kinase (PI3K) inhibitor would promote apoptosis and enhance the impact on glioblastoma cells. The PI3K pathway is commonly activated in glioblastoma and promotes tumor cell survival, suggesting that its inhibition would make cells more sensitive to cytotoxic agents. We chose PX-866 as a PI3K inhibitor as it is a clinically promising agent being evaluated for brain tumor therapy. Combining BBR3610 and PX-866 resulted in synergistic killing of cultured glioma cells and an extension of survival in an orthotopic xenograft animal model. Both agents alone induced autophagy, and this appeared to be saturated, because when they were combined no additional autophagy was observed. However, the combination of PX-866 and BBR3610 did induce statistically significant increases in the level of apoptosis, associated with a reduction in pAkt and pBad, as well as inhibition of transwell migration. We conclude that combining polynuclear platinums with PI3K inhibitors has translational potential and alters the cellular response to include early apoptosis.
authors.affiliation: Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Ho-Shin
authors.initials: HS
authors.lastname: Gwak
authors.forename: Takashi
authors.initials: T
authors.lastname: Shingu
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Chumbalkar
authors.forename: Yeo-Hyeon
authors.initials: YH
authors.lastname: Hwang
authors.forename: Robert
authors.initials: R
authors.lastname: DeJournett
authors.forename: Khatri
authors.initials: K
authors.lastname: Latha
authors.forename: Dimpy
authors.initials: D
authors.lastname: Koul
authors.forename: W K
authors.initials: WK
authors.lastname: Alfred Yung
authors.forename: Garth
authors.initials: G
authors.lastname: Powis
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Farrell
authors.forename: Oliver
authors.initials: O
authors.lastname: Bögler
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006067:Gonanes / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: C523470:BBR3610; D006067:Gonanes; D009944:Organoplatinum Compounds; C496788:PX-866; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; D051057:Proto-Oncogene Proteins c-akt
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