Roles of PI3-K/Akt pathways in nanoparticle realgar powders-induced apoptosis in U937 cells.

Abstract

AIM:

To study the mechanism by which nanoparticle realgar powders (NRP) induce human histocytic lymphoma U937 cell apoptosis.

METHODS:

After the U937 cells were treated with various doses of NRP, the viability of the NRP-induced U937 cells was detected by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Granular apoptotic bodies with membrane blebbing and condensed nuclei were observed by fluorescence microscopy. The apoptotic ratio induced by NRP was measured by lactate dehydrogenase (LDH) activity-based assay. Caspase-3 and the expressions of Akt, p-Akt, a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase (SIRT1), p53, and p-p53 were detected by Western blot analysis.

RESULTS:

The growth-inhibitory activity of NRP for U937 cells was in a time- and dose-dependent manner. After treatment with various concentrations of NRP for 24 h, the majority of U937 cells underwent apoptosis as measured by LDH assay. In the presence of NRP, wortmannin, the inhibitor of phosphoinositide 3-kinase (PI3-K), and Akt inhibitor KP372-1 augmented the NRP-induced cell apoptosis. When the U937 cells were treated with NRP for the indicated time periods, procaspase-3 was gradually degraded and the activated caspase-3 was significantly increased. The expressions of anti-apoptotic proteins Akt and p-Akt were downregulated. Importantly, the inhibition of SIRT1 contributed to the activation of p53 and the inactivation of the PI3-K/Akt signaling pathway increased the expression of the p53 protein and downregulated the SIRT1 protein expression.

CONCLUSION:

The PI3-K/Akt signaling pathway plays an important role in NRP-induced U937 cell apoptosis. The reduced SIRT1 expression and activated p53 might be partially due to the inhibition of the PI3-K/Akt pathway triggered by the NRP-induced initiation of U937 cell apoptosis.

• Authors: Rong-gang Xi, Jian Huang, Dan Li, Xiao-bo Wang, Li-jun Wu
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 29 Issue 3 Pg. 355-63 (Mar 2008) ISSN: 1745-7254 [Electronic] United States
• PMID: 18298901 (Publication Type: Journal Article)

Chemical References

• Arsenicals
• Powders
• Sulfides
• arsenic disulfide
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Apoptosis (drug effects)
• Arsenicals (pharmacology)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Humans
• Nanoparticles (chemistry)
• Particle Size
• Phosphatidylinositol 3-Kinases (metabolism)
• Powders
• Proto-Oncogene Proteins c-akt (metabolism)
• Sulfides (pharmacology)
• Time Factors
• U937 Cells