Catharanthine, an anticancer vinca alkaloid: an in silico and in vitro analysis of the autophagic system as the major mechanism of cell death in liver HepG2 cells.

Autor: Gholami F; Department of Molecular and Cell Biology, Faculty of Basic Sciences, University of Mazandaran, Babolsar, Iran., Seyedalipour B; Department of Molecular and Cell Biology, Faculty of Basic Sciences, University of Mazandaran, Babolsar, Iran., Heidari-Kalvani N; Department of Biochemistry, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran., Nabi-Afjadi M; Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran., Yaghoubzad-Maleki M; Division of Biochemistry, Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran., Fathi Z; School of Medicine, Tehran University of Medical Sciences, Tehran, Iran., Alipourfard I; Institute of Physical Chemistry, Polish Academy of Sciences, Warsaw, Poland., Barjesteh F; Department of Biochemistry, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran., Bahreini E; Department of Biochemistry, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran. Bahreini.e@iums.ac.ir.
Jazyk: angličtina
Zdroj: Naunyn-Schmiedeberg's archives of pharmacology [Naunyn Schmiedebergs Arch Pharmacol] 2024 Nov; Vol. 397 (11), pp. 8879-8892. Date of Electronic Publication: 2024 Jun 10.
DOI: 10.1007/s00210-024-03191-8
Abstrakt: Catharanthine, a component of the anticancer drug vinblastine along with vindoline, disrupts the cell cycle by interfering with mitotic spindle formation. Apart from their antioxidant properties, vinca alkaloids like catharanthine inhibit phosphodiesterase activity and elevate intracellular cAMP levels. The aim of this study was to investigate how catharantine affects apoptosis and autophagy. This study conducted experiments on HepG2 liver carcinoma cells with varying doses of catharanthine to evaluate cell death rates and viability and determine the IC 50  concentration via MTT assays. The apoptotic and autophagic effects of catharanthine were assessed using flow cytometry with annexin V and PI staining, while the expression of autophagy-related genes was analyzed through quantitative PCR. Additionally, molecular docking and molecular dynamics simulations were employed to further investigate catharanthine's impact on autophagy mechanisms. The study showed that catharanthine reduced oxidative stress and triggered apoptosis in HepG2 cells in a dose-dependent manner. Catharanthine also upregulated the expression of autophagy-related genes like LC3, Beclin1, and ULK1. Notably, catharanthine increased sirtuin-1 levels, a known autophagy inducer, while decreasing Akt expression compared to untreated cells. Molecular docking results indicated rapamycin had a stronger binding affinity with FRB (-10.7 KJ/mol -1 ) than catharanthine (-7.3 KJ/mol -1 ). Additionally, molecular dynamics simulations revealed that catharanthine interacted effectively with the FRB domain of mTOR, displaying stability and a strong binding affinity, although not as potent as rapamycin. In summary, besides its cytotoxic and pro-apoptotic effects, catharanthine activates autophagy signaling pathways and induces autophagic necrosis by inhibiting mTOR.
(© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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