TY - JOUR
T1 - Inhibition study on insulin fibrillation and cytotoxicity by paclitaxel
AU - Kachooei, Ehsan
AU - Moosavi-Movahedi, Ali Akbar
AU - Khodagholi, Fariba
AU - Mozaffarian, Faroogh
AU - Sadeghi, Payam
AU - Hadi-Alijanvand, Hamid
AU - Ghasemi, Atiyeh
AU - Saboury, Ali Akbar
AU - Farhadi, Mohammad
AU - Sheibani, Nader
PY - 2014/6
Y1 - 2014/6
N2 - 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.
AB - 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.
KW - cytotoxicity
KW - inhibition
KW - insulin fibrillation
KW - nucleation
KW - paclitaxel
UR - http://www.scopus.com/inward/record.url?scp=84901854510&partnerID=8YFLogxK
U2 - 10.1093/jb/mvu012
DO - 10.1093/jb/mvu012
M3 - Article
C2 - 24535601
AN - SCOPUS:84901854510
SN - 0021-924X
VL - 155
SP - 361
EP - 373
JO - Journal of Biochemistry
JF - Journal of Biochemistry
IS - 6
ER -