Related Experiment Video
Updated: Jun 6, 2025
Method for Identifying Small Molecule Inhibitors of the Protein-protein Interaction Between HCN1 and TRIP8b
Published on: November 11, 2016
Hit Identification and Functional Validation of Novel Dual Inhibitors of HDAC8 and Tubulin Identified by Combining
Antonio Curcio1, Roberta Rocca1,2,3, Federica Chiera1
1Department of Health Sciences, University Magna Græcia, 88100 Catanzaro, Italy.
Abstract:
Chromatin organization, which is under the control of histone deacetylases (HDACs), is frequently deregulated in cancer cells. Amongst HDACs, HDAC8 plays an oncogenic role in different neoplasias by acting on both histone and non-histone substrates. Promising anti-cancer strategies have exploited dual-targeting drugs that inhibit both HDAC8 and tubulin. These drugs have shown the potential to enhance the outcome of anti-cancer treatments by simultaneously targeting multiple pathways critical to disease onset and progression. In this study, a structure-based virtual screening (SBVS) of 96403 natural compounds was performed towards the four Class I HDAC isoforms and tubulin. Using molecular docking and molecular dynamics simulations (MDs), we identified two molecules that could selectively interact with HDAC8 and tubulin. CNP0112925 (arundinin), bearing a polyphenolic structure, was confirmed to inhibit HDAC8 activity and tubulin organization, affecting breast cancer cell viability and triggering mitochondrial superoxide production and apoptosis.
Insights
This study identifies a natural compound, arundinin, that inhibits both HDAC8 and tubulin, crucial targets in cancer. Arundinin effectively reduces breast cancer cell viability and induces apoptosis, offering a promising dual-targeting anti-cancer strategy.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Histone deacetylases (HDACs) regulate chromatin organization and are often deregulated in cancer.
- HDAC8 specifically plays an oncogenic role by targeting both histone and non-histone substrates.
- Dual-targeting drugs inhibiting HDAC8 and tubulin represent a promising anti-cancer strategy.
Purpose of the Study:
- To identify novel natural compounds that can selectively inhibit HDAC8 and tubulin.
- To evaluate the anti-cancer potential of identified compounds against breast cancer cells.
Main Methods:
- Structure-based virtual screening (SBVS) of 96,403 natural compounds against HDAC Class I isoforms and tubulin.
- Molecular docking and molecular dynamics simulations (MDs) to assess compound-target interactions.
- In vitro assays to confirm compound activity on HDAC8, tubulin organization, and cancer cell viability.
Main Results:
- Two compounds selectively interacting with HDAC8 and tubulin were identified.
- CNP0112925 (arundinin), a polyphenolic compound, demonstrated inhibition of HDAC8 activity and tubulin organization.
- Arundinin treatment reduced breast cancer cell viability and induced apoptosis via mitochondrial superoxide production.
Conclusions:
- Arundinin is a potent dual inhibitor of HDAC8 and tubulin.
- This compound shows significant anti-cancer effects in breast cancer models.
- Arundinin represents a promising therapeutic candidate for dual-targeting cancer therapy.
