Antitumor activity of NVP-BKM120--a selective pan class I PI3 kinase inhibitor showed differential forms of cell death based on p53 status of glioma cells.

Abstract

PURPOSE:

The aim of this study was to show preclinical efficacy and clinical development potential of NVP-BKM120, a selective pan class I phosphatidylinositol-3 kinase (PI3K) inhibitor in human glioblastoma (GBM) cells in vitro and in vivo.

EXPERIMENTAL DESIGN:

The effect of NVP-BKM120 on cellular growth was assessed by CellTiter-Blue assay. Flow cytometric analyses were carried out to measure the cell-cycle, apoptosis, and mitotic index. Mitotic catastrophe was detected by immunofluorescence. The efficacy of NVP-BKM120 was tested using intracranial U87 glioma model.

RESULTS:

We tested the biologic effects of a selective PI3K inhibitor NVP-BKM120 in a set of glioma cell lines. NVP-BKM120 treatment for 72 hours resulted in a dose-dependent growth inhibition and effectively blocked the PI3K/Akt signaling cascade. Although we found no obvious relationship between the cell line's sensitivity to NVP-BKM120 and the phosphatase and tensin homolog (PTEN) and epidermal growth factor receptor (EGFR) statuses, we did observe a differential sensitivity pattern with respect to p53 status, with glioma cells containing wild-type p53 more sensitive than cells with mutated or deleted p53. NVP-BKM120 showed differential forms of cell death on the basis of p53 status of the cells with p53 wild-type cells undergoing apoptotic cell death and p53 mutant/deleted cells having a mitotic catastrophe cell death. NVP-BKM120 mediates mitotic catastrophe mainly through Aurora B kinase. Knockdown of p53 in p53 wild-type U87 glioma cells displayed microtubule misalignment, multiple centrosomes, and mitotic catastrophe cell death. Parallel to the assessment of the compound in in vitro settings, in vivo efficacy studies using an intracranial U87 tumor model showed an increased median survival from 26 days (control cohort) to 38 and 48 days (treated cohorts).

CONCLUSION:

Our present findings establish that NVP-BKM120 inhibits the PI3K signaling pathways, leading to different forms of cell death on the basis of p53 statuses. Further studies are warranted to determine if NVP-BKM120 has potential as a glioma treatment.

• Authors: Dimpy Koul, Jun Fu, Ruijun Shen, Tiffany A LaFortune, Shuzhen Wang, Ningyi Tiao, Yong-Wan Kim, Juinn-Lin Liu, Deepti Ramnarian, Ying Yuan, Carlos Garcia-Echevrria, Sauveur-Michel Maira, W K Alfred Yung
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 1 Pg. 184-95 (Jan 01 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22065080 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 AACR.

Chemical References

• Aminopyridines
• Enzyme Inhibitors
• Morpholines
• NVP-BKM120
• Phosphoinositide-3 Kinase Inhibitors
• RNA, Messenger
• Tumor Suppressor Protein p53

Topics

• Aminopyridines (pharmacology)
• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Brain Neoplasms (drug therapy, enzymology, pathology)
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Enzyme Inhibitors (pharmacokinetics, pharmacology)
• Fluorescent Antibody Technique
• Glioma (drug therapy, enzymology, pathology)
• Humans
• Immunoenzyme Techniques
• Mice
• Mice, Nude
• Morpholines (pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Tissue Distribution
• Tumor Cells, Cultured
• Tumor Suppressor Protein p53 (genetics, metabolism)