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Updated: May 3, 2026
Long-term Live-cell Imaging to Assess Cell Fate in Response to Paclitaxel
Published on: May 14, 2018
Inhibition study on insulin fibrillation and cytotoxicity by paclitaxel
Ehsan Kachooei1, Ali Akbar Moosavi-Movahedi2, Fariba Khodagholi1
1Institute 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.
Insights
Paclitaxel inhibits insulin fibrillation, a key process in neurodegenerative diseases like Alzheimer's. This polyphenol protects cells from toxic protein aggregates by altering protein interactions.
Area of Science:
- Biochemistry
- Neuroscience
- Pharmacology
Background:
- Protein aggregation into amyloid fibrils is linked to Alzheimer's and other pathologies.
- Inhibiting this fibrillation is a therapeutic target, with peptides and small molecules previously explored.
- Paclitaxel, a polyphenol, interacts with proteins and was investigated for its anti-fibrillation properties.
Purpose of the Study:
- To investigate the effect of paclitaxel on insulin fibrillation using insulin as a model protein.
- To elucidate the molecular mechanisms underlying paclitaxel's interaction with insulin.
- To assess paclitaxel's protective effects on neuronal cells against insulin fibril toxicity.
Main Methods:
- Thioflavin T fluorescence, Congo red absorbance, circular dichroism, and atomic force microscopy were used to study fibrillation.
- Isothermal titration calorimetry (ITC) analyzed the binding interaction between paclitaxel and insulin.
- Molecular dynamic simulations and docking studies explored the interaction at a molecular level.
- PC12 cell-based assays evaluated the impact on neurite outgrowth and cell survival.
Main Results:
- Paclitaxel significantly inhibited insulin nucleation and fibrillation in a dose-dependent manner.
- ITC revealed a spontaneous interaction between paclitaxel and insulin, driven by van der Waals forces and hydrogen bonds.
- Computational studies showed paclitaxel increases insulin dimer hydrophobicity, reducing polarity and electrostatic interactions.
- Paclitaxel mitigated the disruptive effects of insulin fibrils on PC12 cell neurite outgrowth and enhanced cell survival.
Conclusions:
- Paclitaxel acts as an effective inhibitor of insulin fibrillation by interfering with nucleation.
- The interaction between paclitaxel and insulin is spontaneous and involves hydrophobic and hydrogen bonding.
- Paclitaxel demonstrates neuroprotective potential by reducing fibril toxicity and promoting neuronal health.
