Title:The Interaction of the Microtubule Targeting Anticancer Drug Colchicine with Human Glutathione Transferases
Volume: 26
Issue: 40
Author(s): Georgios Premetis, Panagiotis Marugas, Georgios Fanos, Dimitrios Vlachakis, Evangelia G. Chronopoulou, Fereniki Perperopoulou, Kashyap Kumar Dubey, Pratyoosh Shukla, Ahmed Ibrahim Foudah, Magdy Mohamed Muharram, Mohammed F. Aldawsari, Anastassios C. Papageorgiou and Nikolaos E. Labrou*
Affiliation:
- Laboratory of Enzyme Technology, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 75 Iera Odos Street, GR-11855-Athens,Greece
Keywords:
Cancer, colchicine, glutathione transferase, multi-drug resistance, Phase II detoxification enzymes, antimitotic.
Abstract:
Background: Glutathione transferases (GSTs) are a family of Phase II detoxification enzymes that
have been shown to be involved in the development of multi-drug resistance (MDR) mechanism toward chemotherapeutic
agents. GST inhibitors have, therefore, emerged as promising chemosensitizers to manage and
reverse MDR. Colchicine (COL) is a classical antimitotic, tubulin-binding agent (TBA) which is being explored
as anticancer drug.
Methods: In the present work, the interaction of COL and its derivative 2,3-didemethylcolchicine (2,3-DDCOL)
with human glutathione transferases (hGSTA1-1, hGSTP1-1, hGSTM1-1) was investigated by inhibition analysis,
molecular modelling and molecular dynamics simulations.
Results: The results showed that both compounds bind reversibly to human GSTs and behave as potent inhibitors.
hGSTA1-1 was the most sensitive enzyme to inhibition by COL with IC50 22 μΜ. Molecular modelling predicted
that COL overlaps with both the hydrophobic (H-site) and glutathione binding site (G-site) and polar interactions
appear to be the driving force for its positioning and recognition at the binding site. The interaction of COL with
other members of GST family (hGSTA2-2, hGSTM3-3, hGSTM3-2) was also investigated with similar results.
Conclusion: The results of the present study might be useful in future drug design and development efforts towards
human GSTs.