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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

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Flavonoids as potential reactivators of structural mutation p53Y220C by computational and cell-based studies

Lakshay Malhotra1,2, Punit Kaur1, Abdul Samath Ethayathulla1

  • 1Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India.

Journal of Biomolecular Structure & Dynamics
|August 29, 2023
PubMed

Insights

Certain flavonoids, specifically MPA and MPB, can restore the function of the p53 Y220C cancer mutation. These compounds show therapeutic potential for stabilizing the mutant p53 protein and could be used in cancer treatment.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • The p53 Y220C mutation is a common structural alteration in human cancers, leading to the loss of tumor suppressor activity.
  • This mutation destabilizes the p53 protein by allowing solvent entry into its DNA binding domain, creating a targetable crevice.
  • Previous research demonstrated Curcumin's ability to restore p53 Y220C function in pancreatic cancer cells.

Purpose of the Study:

  • To evaluate the potential of six Curcumin-like flavonoids (Apigenin, Isoliquiritigenin, Liquiritigenin, Luteolin, MPA, and MPB) in restoring the function of the p53 Y220C mutant.
  • To investigate the molecular mechanisms underlying the interaction of these flavonoids with the p53 Y220C mutant.
  • To assess the in vitro efficacy of these compounds in inducing cytotoxicity in cancer cells harboring the p53 Y220C mutation.

Main Methods:

  • Molecular docking simulations to predict binding interactions within the p53 Y220C crevice.
  • Molecular dynamics (MD) simulations to analyze the stability of the p53 DNA binding domain upon compound interaction.
  • Cell-based cytotoxicity assays using BxPC-3 pancreatic cancer cells with the p53 Y220C mutation.

Main Results:

  • MD simulations indicated that the tested flavonoids could stabilize the mutant p53 DNA binding domain towards a wild-type-like structure.
  • The flavonoids Methylophiopogonanone A (MPA) and Methylophiopogonanone B (MPB) demonstrated significant cytotoxicity, causing 75% cell death at 100 µM in BxPC-3 cells.
  • These findings suggest a structure-restoring mechanism for MPA and MPB on the p53 Y220C mutant.

Conclusions:

  • The flavonoids MPA and MPB exhibit therapeutic potential for restoring the function of the p53 Y220C mutant.
  • MPA and MPB could serve as novel therapeutic agents for cancers with the p53 Y220C mutation.
  • These compounds may be valuable in combinatorial therapy strategies to enhance efficacy and reduce drug dosage.
Keywords:
cytotoxicityflavonoidsmolecular dockingp53Y220Cpancreatic cancer

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