Inhibition study on insulin fibrillation and cytotoxicity by paclitaxel

Kachooei, E. and Moosavi-Movahedi, A.A. and Khodagholi, F. and Mozaffarian, F. and Sadeghi, P. and Hadi-Alijanvand, H. and Ghasemi, A. and Saboury, A.A. and Farhadi, M. and Sheibani, N. (2014) Inhibition study on insulin fibrillation and cytotoxicity by paclitaxel. Journal of Biochemistry, 155 (6). pp. 361-373.

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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. © 2014 The Authors 2014.

Item Type: Article
Additional Information: cited By 16
Uncontrolled Keywords: amyloid; congo red; dimer; insulin; paclitaxel; thioflavine; amyloid; insulin; paclitaxel; thiazole derivative, animal cell; article; atomic force microscopy; beta sheet; cell differentiation; cell growth; cell survival; cell viability; circular dichroism; controlled study; dipole; drug cytotoxicity; drug effect; fluorescence; hormone action; hydrogen bond; hydrophobicity; insulin fibrillation; insulin treatment; isothermal titration calorimetry; MTT assay; nerve fiber growth; nonhuman; protein secondary structure; static electricity; animal; chemistry; dose response; drug effects; metabolism; molecular dynamics; PC12 cell line; protein multimerization; rat, Amyloid; Animals; Cell Differentiation; Circular Dichroism; Dose-Response Relationship, Drug; Fluorescence; Hydrogen Bonding; Insulin; Microscopy, Atomic Force; Molecular Dynamics Simulation; Paclitaxel; PC12 Cells; Protein Multimerization; Protein Structure, Secondary; Rats; Thiazoles
Subjects: QV Pharmacology
Depositing User: Ms Roya Vesal Azad
Date Deposited: 26 Feb 2019 09:12
Last Modified: 26 Feb 2019 09:12

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