Related Experiment Video
Updated: Aug 13, 2025
Spectrophotometric Screening for Potential Inhibitors of Cytosolic Glutathione S-Transferases
Published on: October 10, 2020
Monocarbonyl Curcumin Analogues as Potent Inhibitors against Human Glutathione Transferase P1-1
Panagiota Pantiora1,2, Veronika Furlan3, Dimitris Matiadis2
1Laboratory of Enzyme Technology, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 75 Iera Odos Street, GR-11855 Athens, Greece.
Abstract:
The isoenzyme of human glutathione transferase P1-1 (hGSTP1-1) is involved in multi-drug resistance (MDR) mechanisms in numerous cancer cell lines. In the present study, the inhibition potency of two curcuminoids and eleven monocarbonyl curcumin analogues against hGSTP1-1 was investigated. Demethoxycurcumin (Curcumin II) and three of the monocarbonyl curcumin analogues exhibited the highest inhibitory activity towards hGSTP1-1 with IC50 values ranging between 5.45 ± 1.08 and 37.72 ± 1.02 μM. Kinetic inhibition studies of the most potent inhibitors demonstrated that they function as non-competitive/mixed-type inhibitors. These compounds were also evaluated for their toxicity against the prostate cancer cells DU-145. Interestingly, the strongest hGSTP1-1 inhibitor, (DM96), exhibited the highest cytotoxicity with an IC50 of 8.60 ± 1.07 μΜ, while the IC50 values of the rest of the compounds ranged between 44.59-48.52 μΜ. Structural analysis employing molecular docking, molecular dynamics (MD) simulations, and binding-free-energy calculations was performed to study the four most potent curcumin analogues as hGSTP1-1 inhibitors. According to the obtained computational results, DM96 exhibited the lowest binding free energy, which is in agreement with the experimental data. All studied curcumin analogues were found to form hydrophobic interactions with the residue Gln52, as well as hydrogen bonds with the nearby residues Gln65 and Asn67. Additional hydrophobic interactions with the residues Phe9 and Val36 as well as π-π stacking interaction with Phe9 contributed to the superior inhibitory activity of DM96. The van der Waals component through shape complementarity was found to play the most important role in DM96-inhibitory activity. Overall, our results revealed that the monocarbonyl curcumin derivative DM96 acts as a strong hGSTP1-1 inhibitor, exerts high prostate cancer cell cytotoxicity, and may, therefore, be exploited for the suppression and chemosensitization of cancer cells. This study provides new insights into the development of safe and effective GST-targeted cancer chemosensitizers.
Insights
Curcumin analogues, particularly DM96, effectively inhibit human glutathione transferase P1-1 (hGSTP1-1), a key player in cancer drug resistance. These compounds also show potent cytotoxicity against prostate cancer cells, offering potential for new cancer therapies.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Cancer Research
Background:
- Human glutathione transferase P1-1 (hGSTP1-1) is implicated in multi-drug resistance (MDR) in various cancer cell lines.
- Curcuminoids and their analogues are explored for their potential therapeutic properties.
Purpose of the Study:
- To investigate the inhibitory activity of curcuminoids and monocarbonyl curcumin analogues against hGSTP1-1.
- To evaluate the cytotoxicity of these compounds against prostate cancer cells.
- To elucidate the molecular mechanisms underlying the inhibition of hGSTP1-1 by potent curcumin analogues.
Main Methods:
- Enzyme inhibition assays to determine IC50 values.
- Kinetic studies to characterize inhibitor types.
- Cytotoxicity assays against DU-145 prostate cancer cells.
- Molecular docking, molecular dynamics (MD) simulations, and binding-free-energy calculations.
Main Results:
- Demethoxycurcumin and three monocarbonyl curcumin analogues showed significant hGSTP1-1 inhibition (IC50: 5.45–37.72 μM).
- The strongest inhibitor, DM96, exhibited potent cytotoxicity against DU-145 cells (IC50: 8.60 μM).
- Computational analyses revealed DM96's superior binding affinity through hydrophobic interactions and shape complementarity with hGSTP1-1.
Conclusions:
- Monocarbonyl curcumin derivative DM96 is a potent hGSTP1-1 inhibitor with significant prostate cancer cell cytotoxicity.
- DM96 and related compounds show promise for cancer treatment by suppressing and chemosensitizing cancer cells.
- This research provides a foundation for developing novel GST-targeted cancer chemosensitizers.
