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J Biochem. 2014 Jun;155(6):361-73. doi: 10.1093/jb/mvu012. Epub 2014 Feb 17.

Inhibition study on insulin fibrillation and cytotoxicity by paclitaxel.

Author information

1
Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran; Center of Excellence in Biothermodynamics, University of Tehran, Tehran, Iran; NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Biological Sciences, Institute for Advanced Studies in Basic Sciences, Department of Biological Sciences, Zanjan, Iran; ENT-HNS Research Center, IUMS, Tehran, Iran; and Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA.
2
Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran; Center of Excellence in Biothermodynamics, University of Tehran, Tehran, Iran; NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Biological Sciences, Institute for Advanced Studies in Basic Sciences, Department of Biological Sciences, Zanjan, Iran; ENT-HNS Research Center, IUMS, Tehran, Iran; and Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USAInstitute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran; Center of Excellence in Biothermodynamics, University of Tehran, Tehran, Iran; NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Biological Sciences, Institute for Advanced Studies in Basic Sciences, Department of Biological Sciences, Zanjan, Iran; ENT-HNS Research Center, IUMS, Tehran, Iran; and Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA moosavi@ut.ac.ir.
3
Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran; Center of Excellence in Biothermodynamics, University of Tehran, Tehran, Iran; NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Biological Sciences, Institute for Advanced Studies in Basic Sciences, Department of Biological Sciences, Zanjan, Iran; ENT-HNS Research Center, IUMS, Tehran, Iran; and Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USAInstitute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran; Center of Excellence in Biothermodynamics, University of Tehran, Tehran, Iran; NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Biological Sciences, Institute for Advanced Studies in Basic Sciences, Department of Biological Sciences, Zanjan, Iran; ENT-HNS Research Center, IUMS, Tehran, Iran; and Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA.

Abstract

Alzheimer, a neurodegenerative disease, and a large variety of pathologic conditions are associated with a form of protein aggregation known as amyloid fibrils. Since fibrils and prefibrillar intermediates are cytotoxic, numerous attempts have been made to inhibit fibrillation process as a therapeutic strategy. Peptides, surfactants and aromatic small molecules have been used as fibrillation inhibitors. Here we studied the effects of paclitaxel, a polyphenol with a high tendency for interaction with proteins, on fibrillation of insulin as a model protein. The effects of paclitaxel on insulin fibrillation were determined by Thioflavin T fluorescence, Congo red absorbance, circular dichroism and atomic force microscopy. These studies indicated that paclitaxel considerably hindered nucleation, and therefore, fibrillation of insulin in a dose-dependant manner. The isothermal titration calorimetry studies showed that the interaction between paclitaxel and insulin was spontaneous. In addition, the van der Waal's interactions and hydrogen bonds were prominent forces contributing to this interaction. Computational results using molecular dynamic simulations and docking studies revealed that paclitaxel diminished the polarity of insulin dimer and electrostatic interactions by increasing the hydrophobicity of its dimer state. Furthermore, paclitaxel reduced disrupting effects of insulin fibrils on PC12 cell's neurite outgrowth and complexity, and enhanced their survival.

KEYWORDS:

cytotoxicity; inhibition; insulin fibrillation; nucleation; paclitaxel

PMID:
24535601
DOI:
10.1093/jb/mvu012
[Indexed for MEDLINE]
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