Inhibition study on insulin fibrillation and cytotoxicity by paclitaxel

Ehsan Kachooei, Ali Akbar Moosavi-Movahedi, Fariba Khodagholi, Faroogh Mozaffarian, Payam Sadeghi, Hamid Hadi-Alijanvand, Atiyeh Ghasemi, Ali Akbar Saboury, Mohammad Farhadi, Nader Sheibani

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)361-373
Number of pages13
JournalJournal of Biochemistry
Volume155
Issue number6
DOIs
Publication statusPublished - Jun 2014
Externally publishedYes

Keywords

  • cytotoxicity
  • inhibition
  • insulin fibrillation
  • nucleation
  • paclitaxel

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    Kachooei, E., Moosavi-Movahedi, A. A., Khodagholi, F., Mozaffarian, F., Sadeghi, P., Hadi-Alijanvand, H., ... Sheibani, N. (2014). Inhibition study on insulin fibrillation and cytotoxicity by paclitaxel. Journal of Biochemistry, 155(6), 361-373. https://doi.org/10.1093/jb/mvu012