Involvement of PI3K-Akt-Bad pathway in apoptosis induced by 2,6-di-O-methyl-beta-cyclodextrin, not 2,6-di-O-methyl-alpha-cyclodextrin, through cholesterol depletion from lipid rafts on plasma membranes in cells.

Abstract

Cyclodextrins (CyDs), which are widely used to increase the solubility of drug in pharmaceutical fields, are known to induce hemolysis and cytotoxicity at high concentrations. However, it is still not unclear whether cell death induced by CyDs is apoptosis or not. Therefore, in the present study, we investigated the effects of various kinds of CyDs on apoptosis in the cells such as NR8383 cells, A549 cells and Jurkat cells. Of various CyDs, methylated CyDs inducted cell death under the present experimental conditions, but hydroxypropylated CyDs or sulfobutyl ether-beta-CyD (SBE7-beta-CyD) did not. Of methylated CyDs, 2,6-di-O-methyl-beta-cyclodextrin (DM-beta-CyD) and 2,3,6-tri-O-methyl-beta-cyclodextrin (TM-beta-CyD) markedly caused apoptosis in NR8383 cells, A549 cells and Jurkat cells, through cholesterol depletion in cell membranes. In sharp contrast, 2,6-di-O-methyl-alpha-cyclodextrin (DM-alpha-CyD) and methyl-beta-cyclodextrin (M-beta-CyD) induced cell death in an anti-apoptotic mechanism. DM-beta-CyD induced apoptosis through the inhibition of the activation of PI3K-Akt-Bad pathway. Neither p38 MAP kinase nor p53 was contributed to the induction of apoptosis by DM-beta-CyD. Additionally, DM-beta-CyD significantly decreased mitochondrial transmembrane potential, and then caused the release of cytochrome c from mitochondria to cytosol in NR8383 cells. Furthermore, we confirmed that down-regulation of pro-caspase-3 and activation of caspase-3 after incubation with DM-beta-CyD. These results suggest that of methylated CyDs, DM-beta-CyD, not DM-alpha-CyD, induces apoptosis through the PI3K-Akt-Bad pathway, resulting from cholesterol depletion in lipid rafts of cell membranes.

• Authors: Keiichi Motoyama, Kazuhisa Kameyama, Risako Onodera, Norie Araki, Fumitoshi Hirayama, Kaneto Uekama, Hidetoshi Arima
• Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences (Eur J Pharm Sci) Vol. 38 Issue 3 Pg. 249-61 (Oct 08 2009) ISSN: 1879-0720 [Electronic] Netherlands
• PMID: 19664706 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bad protein, mouse
• Phosphoinositide-3 Kinase Inhibitors
• alpha-Cyclodextrins
• bcl-Associated Death Protein
• beta-Cyclodextrins
• heptakis(2,6-O-dimethyl)beta-cyclodextrin
• Cholesterol
• Proto-Oncogene Proteins c-akt
• alpha-cyclodextrin

Topics

• Animals
• Apoptosis (drug effects, physiology)
• Cells, Cultured
• Cholesterol (deficiency)
• Humans
• Jurkat Cells
• Membrane Microdomains (drug effects, physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Phosphatidylinositol 3-Kinases (physiology)
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, physiology)
• Signal Transduction (drug effects, physiology)
• alpha-Cyclodextrins (chemistry, pharmacology)
• bcl-Associated Death Protein (antagonists & inhibitors, physiology)
• beta-Cyclodextrins (chemistry, pharmacology)