Related Experiment Video
Updated: Jul 4, 2025
A Protocol for Rapid Post-mortem Cell Culture of Diffuse Intrinsic Pontine Glioma DIPG
Published on: March 7, 2017
Harmaline to Human Mitochondrial Caseinolytic Serine Protease Activation for Pediatric Diffuse Intrinsic Pontine
Morena Miciaccia1, Francesca Rizzo2, Antonella Centonze1
1Research Laboratory for Woman and Child Health, Department of Pharmacy-Pharmaceutical Sciences, University of Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari, Italy.
Insights
Diffuse intrinsic pontine glioma (DIPG) is a deadly pediatric brain tumor. Harmaline, a new compound, shows promise in activating a key protein target, offering hope for treating ONC201-resistant DIPG.
Area of Science:
- Oncology
- Biochemistry
- Pharmacology
Background:
- Diffuse intrinsic pontine glioma (DIPG) is a rare, aggressive pediatric brain tumor with poor prognosis.
- ONC201, a cytotoxic agent, targets human mitochondrial caseinolytic serine protease type C (hClpP) and has shown efficacy against DIPG cell lines.
- Acquired resistance to ONC201 necessitates the discovery of new therapeutic agents targeting hClpP.
Purpose of the Study:
- To identify novel scaffolds that activate hClpP for treating ONC201-resistant DIPG.
- To investigate the interaction and activation of hClpP by harmaline, a potential new therapeutic agent.
Main Methods:
- Structure-based virtual screening using Fingerprints for Ligands and Proteins (FLAP) to identify potential hClpP activators.
- Molecular dynamics simulations to analyze the interaction between harmaline and hClpP.
- In vitro investigations to assess the activity of harmaline against hClpP.
Main Results:
- Harmaline, a beta-carboline derivative, was identified as a promising hClpP activator.
- Molecular dynamics and in vitro studies provided insights into harmaline's interaction and activation mechanism of hClpP.
- Harmaline represents a potential therapeutic candidate for DIPG patients resistant to ONC201.
Conclusions:
- Harmaline is a novel activator of hClpP, demonstrating potential for treating ONC201-resistant DIPG.
- Further research into harmaline and its derivatives could lead to new therapeutic strategies for pediatric brain tumors.
Abstract:
Diffuse intrinsic pontine glioma (DIPG), affecting children aged 4-7 years, is a rare, aggressive tumor that originates in the pons and then spreads to nearby tissue. DIPG is the leading cause of death for pediatric brain tumors due to its infiltrative nature and inoperability. Radiotherapy has only a palliative effect on stabilizing symptoms. In silico and preclinical studies identified ONC201 as a cytotoxic agent against some human cancer cell lines, including DIPG ones. A single-crystal X-ray analysis of the complex of the human mitochondrial caseinolytic serine protease type C (hClpP) and ONC201 (PDB ID: 6DL7) allowed hClpP to be identified as its main target. The hyperactivation of hClpP causes damage to mitochondrial oxidative phosphorylation and cell death. In some DIPG patients receiving ONC201, an acquired resistance was observed. In this context, a wide program was initiated to discover original scaffolds for new hClpP activators to treat ONC201-non-responding patients. Harmaline, a small molecule belonging to the chemical class of β-carboline, was identified through Fingerprints for Ligands and Proteins (FLAP), a structure-based virtual screening approach. Molecular dynamics simulations and a deep in vitro investigation showed interesting information on the interaction and activation of hClpP by harmaline.
More Related Videos
07:39Co-culture of Glutamatergic Neurons and Pediatric High-Grade Glioma Cells Into Microfluidic Devices to Assess Electrical Interactions
Published on: November 17, 2021
08:34Proton Therapy Delivery and Its Clinical Application in Select Solid Tumor Malignancies
Published on: February 6, 2019