The Interaction of the Microtubule Targeting Anticancer Drug Colchicine with Human Glutathione Transferases

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, GSTM1-1) 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.

Myricetin as a Potential Adjuvant in Chemotherapy: Studies on the Inhibition of Human Glutathione Transferase A1–1

“…The IC50 value for MYR was determined 2.1 ± 0.2 μΜ, suggesting that MYR is a strong inhibitor towards hGSTA1–1. The low IC50 determined for MYR compares favorably to those that have been reported in the literature [ 31 , 35 , 42 , 43 , 44 , 45 , 46 ]. For example, the IC50 values for colchicine [ 43 ], for the synthetic 2-(pyrrolesulfonylmethyl)- n -arylimines, and benzophenones and their carbonyl n -analogues were in the range 22–71 μΜ [ 45 ].…”

“…The low IC50 determined for MYR compares favorably to those that have been reported in the literature [ 31 , 35 , 42 , 43 , 44 , 45 , 46 ]. For example, the IC50 values for colchicine [ 43 ], for the synthetic 2-(pyrrolesulfonylmethyl)- n -arylimines, and benzophenones and their carbonyl n -analogues were in the range 22–71 μΜ [ 45 ]. However, ethacrynic acid inhibits hGSTA1–1 with Ki (μM) of 4.6–6.0 [ 47 ].…”

Calcium Channel Blockers: The Effect of Glutathione S‐Transferase Enzyme Activity and Molecular Docking Studies

“…They also determined that agents 4 and 5 were safe and effective when administered intravenously or orally as an aqueous solution to mice xenografted with A375 human melanoma tumors. In another study, Premetis, et al [81] examined the interaction of colchicine, is a classical antimitotic, and its derivative 2,3didemethylcolchicine with human GST. Also, it was investigated by inhibition analysis and in silico simulations.…”

PPARG and the PTEN-PI3K/AKT Signaling Axis May Cofunction in Promoting Chemosensitivity in Hypopharyngeal Squamous Cell Carcinoma

“…A two-in-one nanoprodrug improves chemosensitivity in prostate cancer cells through increased apoptosis and metastasis inhibition [ 33 ]. PPARG also contributes to cell cycle dysregulation, related to chemosensitivity [ 34 , 35 ], and influences drug detoxification processes, affecting chemotherapy efficacy [ 36 , 37 ]. Moreover, PPARG's involvement in the inflammatory response is critical for determining chemosensitivity [ 38 , 39 ].…”