| Combined action of the dinuclear platinum compound BBR3610 with the PI3-K inhibitor PX-866 in glioblastoma. | |
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MedLine Citation:
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PMID: 20473884 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Ho-Shin Gwak; Takashi Shingu; Vaibhav Chumbalkar; Yeo-Hyeon Hwang; Robert DeJournett; Khatri Latha; Dimpy Koul; W K Alfred Yung; Garth Powis; Nicholas P Farrell; Oliver Bögler |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: International journal of cancer. Journal international du cancer Volume: 128 ISSN: 1097-0215 ISO Abbreviation: Int. J. Cancer Publication Date: 2011 Feb |
Date Detail:
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Created Date: 2010-12-24 Completed Date: 2011-01-31 Revised Date: 2012-05-23 |
Medline Journal Info:
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Nlm Unique ID: 0042124 Medline TA: Int J Cancer Country: United States |
Other Details:
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Languages: eng Pagination: 787-96 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 UICC. |
Affiliation:
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Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / drug effects Autophagy / drug effects Blotting, Western Brain Neoplasms / drug therapy*, metabolism, pathology Cell Adhesion / drug effects Cell Cycle / drug effects Cell Movement / drug effects Cell Proliferation / drug effects Drug Synergism Drug Therapy, Combination Glioma / drug therapy*, metabolism, pathology Gonanes / therapeutic use* Humans Male Mice Mice, Nude Organoplatinum Compounds / therapeutic use* Phosphatidylinositol 3-Kinases / antagonists & inhibitors Proto-Oncogene Proteins c-akt RNA, Messenger / genetics Reverse Transcriptase Polymerase Chain Reaction Signal Transduction / drug effects Survival Rate Tumor Cells, Cultured |
| Grant Support | |
ID/Acronym/Agency:
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1P50CA127001/CA/NCI NIH HHS; P50 CA127001-020002/CA/NCI NIH HHS; R01 CA128991/CA/NCI NIH HHS; R01 CA128991-01A1/CA/NCI NIH HHS; R01 CA128991-04/CA/NCI NIH HHS; R01CA052995/CA/NCI NIH HHS; R01CA128991/CA/NCI NIH HHS; R21 CA108499-01A1/CA/NCI NIH HHS; R21CA1108499/CA/NCI NIH HHS; U01 CA052995-02/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/BBR3610; 0/Gonanes; 0/Organoplatinum Compounds; 0/PX-866; 0/RNA, Messenger; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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