Lansoprazole as a potent HDAC2 inhibitor for treatment of colorectal cancer: An in-silico analysis and experimental validation.

Autor: Khadempar S; Department of Medical Genetics, Shahid Sadoughi University of Medical Science, Yazd, Iran. Electronic address: s.khadempar@yahoo.com., Lotfi M; Abortion Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Science, Yazd, Iran. Electronic address: Marzeih.lotfi@gmail.com., Haghiralsadat F; Medical Nanotechnology & Tissue Engineering Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran. Electronic address: fhaghirosadat@gmail.com., Saidijam M; Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran., Ghasemi N; Abortion Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Science, Yazd, Iran. Electronic address: nghasemi479@gmail.com., Afshar S; Cancer Research Center, Hamadan University of Medical Sciences, Hamadan, Iran. Electronic address: safshar.h@gmail.com.
Jazyk: angličtina
Zdroj: Computers in biology and medicine [Comput Biol Med] 2023 Nov; Vol. 166, pp. 107518. Date of Electronic Publication: 2023 Sep 27.
DOI: 10.1016/j.compbiomed.2023.107518
Abstrakt: Background: Histone deacetylase 2 (HDAC2), belonging to the class I HDAC family, holds significant therapeutic potential as a crucial target for diverse cancer types. As key players in the realm of epigenetic regulatory enzymes, histone deacetylases (HDACs) are intricately involved in the onset and progression of cancer. Consequently, pursuing isoform-specific inhibitors targeting histone deacetylases (HDACs) has garnered substantial interest in both biological and medical circles. The objective of the present investigation was to employ a drug repurposing approach to discover novel and potent HDAC2 inhibitors.
Materials and Methods: In this study, our protocol is presented on virtual screening to identify novel potential HDAC2 inhibitors through 3D-QSAR, molecular docking, pharmacophore modeling, and molecular dynamics (MD) simulation. Afterward, In-vitro assays were employed to evaluate the cytotoxicity, apoptosis, and migration of HCT-116 cell lines under treatment of hit compound and valproic acid as a control inhibitor. The expression levels of HDAC2, TP53, BCL2, and BAX were evaluated by QRT-PCR.
Results: RMSD, RMSF, H-bond, and DSSP analysis results confirmed that among bioinformatically selected compounds, lansoprazole exhibited the highest HDAC2 inhibitory potential. Experimental validation revealed that lansoprazole displayed significant antiproliferative activity. The determined IC 50 value was 400 ± 2.36 μM. Furthermore, the apoptotic cells ratio concentration-dependently increased under Lansoprazole treatment. Results of the Scratch assay indicated that lansoprazole led to decreasing the migration of CRC cells. Finally, under Lansoprazole treatment the expression level of BCL2 and HDAC2 decreased and BAX and TP53 increased.
Conclusion: Taking together the results of the current study indicated that Lansoprazole as a novel HDAC2 inhibitor, could be used as a potential therapeutic agent for the treatment of CRC. Although, further experimental studies should be performed before using this compound in the clinic.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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