Molecular basis of anti-apoptotic effect of immunophilin ligands on hydrogen peroxide-induced apoptosis in human glioma cells.
To clarify the molecular basis of the cytoprotective properties of immunophilin ligands (IPLs), the anti-apoptotic effects of IPLs were determined in human glioma U251 cells. GPI1046 and V10367, non-immunosuppressive IPLs (NI-IPLs), as well as FK506, an immunosuppressive IPL (I-IPL), had cytoprotective effects against hydrogen peroxide (H20O)-induced apoptotic cell death in U251 cells. H2O2 increased both the ratio of bax/bcl-2 and the p53 mRNA expression. However, pre-treatment with FK506 and V10367 significantly prevented any increase in this ratio or p53 mRNA expression. GPI1046 also reduced the ratio of bax/bcl-2 to the normal level. In addition, H2O2 significantly increased activities of all three caspases, caspase-3, caspase-8, and caspase-9, in comparison with non-H2O2 controls. However, FK506 prevented the increase of these caspase activities. On the other hand, it is well-known that glutathione (GSH) and neurotrophic factor (NTF) is related to the induction of apoptosis in neuronal cells. In U251 cells, FK506, GPI1046 and V10367 had GSH-activating and NTF-activating effects. Thus, the immunosuppressive effect is not essential for the cytoprotective properties of IPLs, and IPLs have multiple beneficial properties such as the anti-apoptotic effect, GSH-activating effect, and NTF-activating effect, although the anti-apoptotic effect of NI-IPLs is independent of the regulation of apoptotic activators such as caspase-3.
Tanaka
Ken-ichi
K
Department of Clinical Pharmacy, Shujitsu University School of Pharmacy, 1-6-1 Nishigawara, Okayama 703-8516, Japan. kntanaka@shujitsu.ac.jp
Asanuma
Masato
M
Ogawa
Norio
N
D017209:Apoptosis / Q000187:drug effects*; D001932:Brain Neoplasms; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D051100:Glial Cell Line-Derived Neurotrophic Factor; D005910:Glioma; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D020104:Immunophilins / Q000502:physiology*; D008024:Ligands; D009414:Nerve Growth Factors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D016559:Tacrolimus / Q000494:pharmacology*
D019208:Brain-Derived Neurotrophic Factor; C495039:GDNF protein, human; C104949:GPI 1046; D051100:Glial Cell Line-Derived Neurotrophic Factor; D008024:Ligands; D009414:Nerve Growth Factors; D011725:Pyridines; D011759:Pyrrolidines; C108850:V 10367; D006861:Hydrogen Peroxide; D020104:Immunophilins; D005978:Glutathione; D016559:Tacrolimus