Inhibitory effects of 1,25-dihydroxyvitamin D3 and its low-calcemic analogues on staurosporine-induced apoptosis.

Abstract

The active form of vitamin D3 and some of its related compounds show neuroprotective effects in various models of neuronal damage, however, mechanism of their anti-apoptotic action has not been elucidated. Therefore, the present study was designed to investigate the effects of 1,25-dihydroxyvitamin D3 and its low-calcemic analogues, PRI-2191, PRI-1890 and PRI-1901 on staurosporine-induced apoptosis in human neuroblastoma SH-SY5Y cells. Twenty-four hour incubation with staurosporine (1 microM) enhanced the caspase-3 activity, decreased mitochondrial membrane potential and increased the number of apoptotic cells as visualized by Hoechst staining. 1,25-Dihydroxyvitamin D3 and PRI-2191 attenuated the staurosporine-induced caspase-3 activity at 5, 50 and 500 nM, whereas PRI-1890 and PRI-1901 were active only at higher concentrations. Furthermore, 1,25-dihydroxyvitamin D3 (50 and 500 nM) and PRI-2191 (500 but not 50 nM) reversed the staurosporine-evoked decrease in mitochondrial membrane potential. Hoechst and calcein staining confirmed the neuroprotective effects of the secosteroids under study. Further study revealed that a selective inhibitor of phosphatidylinositol 3-kinase (PI3-K), wortmannin, at concentration of 100 nM antagonized the effect of 1,25-dihydroxyvitamin D3 and PRI-2191 on staurosporine-induced caspase-3 activation. These data indicate that 1,25-dihydroxyvitamin D3 and its low-calcemic analogues at nanomolar concentrations inhibited mitochondrial pathway of apoptosis in SH-SY5Y neuronal cells, though with different potency. Moreover, the activation of PI3-K/Akt signaling pathway appears to play a role in anti-apoptotic effects of the secosteroids.

• Authors: Magdalena Regulska, Monika Leśkiewicz, Bogusława Budziszewska, Andrzej Kutner, Danuta Jantas, Agnieszka Basta-Kaim, Marta Kubera, Lucylla Jaworska-Feil, Władysław Lasoń
• Journal: Pharmacological reports : PR (Pharmacol Rep) 2007 Jul-Aug Vol. 59 Issue 4 Pg. 393-401 ISSN: 1734-1140 [Print] Switzerland
• PMID: 17901567 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Androstadienes
• Caspase Inhibitors
• Dihydroxycholecalciferols
• Oligopeptides
• PRI 1901
• Phosphoinositide-3 Kinase Inhibitors
• Secosteroids
• acetyl-aspartyl-glutamyl-valyl-aspartal
• 1 alpha,24-dihydroxyvitamin D3
• Caspase 3
• Calcitriol
• Staurosporine
• Wortmannin

Topics

• Androstadienes (pharmacology)
• Apoptosis (drug effects)
• Calcitriol (analogs & derivatives, chemistry, pharmacology)
• Caspase 3 (metabolism)
• Caspase Inhibitors
• Cell Line, Tumor
• Cell Survival (drug effects)
• Dihydroxycholecalciferols (chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Enzyme-Linked Immunosorbent Assay
• Humans
• Membrane Potential, Mitochondrial (drug effects)
• Oligopeptides (pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Secosteroids (chemistry, pharmacology)
• Signal Transduction (drug effects)
• Staurosporine (pharmacology)
• Time Factors
• Wortmannin