Inhibition study on insulin fibrillation and cytotoxicity by paclitaxel

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 therapeut...

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Published in:Journal of biochemistry (Tokyo) 2014-06, Vol.155 (6), p.361-373
Main Authors: Kachooei, Ehsan, Moosavi-Movahedi, Ali Akbar, Khodagholi, Fariba, Mozaffarian, Faroogh, Sadeghi, Payam, Hadi-Alijanvand, Hamid, Ghasemi, Atiyeh, Saboury, Ali Akbar, Farhadi, Mohammad, Sheibani, Nader
Format: Article
Language:English
Subjects:
Amyloid - drug effects
Amyloid - metabolism
Animals
Cell Differentiation - drug effects
Circular Dichroism
Dose-Response Relationship, Drug
Fluorescence
Hydrogen Bonding
Insulin - chemistry
Insulin - metabolism
Microscopy, Atomic Force
Molecular Dynamics Simulation
Paclitaxel - pharmacology
PC12 Cells
Protein Multimerization
Protein Structure, Secondary
Rats
Thiazoles
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Summary: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.
ISSN:0021-924X
1756-2651
DOI:10.1093/jb/mvu012