In vitro and computational studies showed that perezone inhibits PARP-1 and induces changes in the redox state of K562 cells
| Autor: | María Inés Nicolás Vázquez, Erika Rosales Cruz, Elvia Mera Jiménez, Maricarmen Hernández-Rodríguez, Martha Edith Macías Pérez, René Miranda Ruvalcaba, Pablo I. Mendoza Sánchez |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Programmed cell death Cell Survival Poly ADP ribose polymerase Cell Biophysics Poly (ADP-Ribose) Polymerase-1 Apoptosis Asteraceae Molecular Dynamics Simulation Poly(ADP-ribose) Polymerase Inhibitors Biochemistry 03 medical and health sciences medicine Humans Molecular Biology Cell Proliferation 030102 biochemistry & molecular biology Chemistry Cell Cycle Cell cycle In vitro Molecular Docking Simulation 030104 developmental biology medicine.anatomical_structure Mechanism of action medicine.symptom K562 Cells Oxidation-Reduction Sesquiterpenes K562 cells |
| Zdroj: | Archives of biochemistry and biophysics. 671 |
| ISSN: | 1096-0384 |
| Popis: | Cancer is one of the leading causes of morbidity and mortality worldwide. This disease is characterized by uncontrolled growth and proliferation of abnormal cells with a high probability to develop metastasis. Recently, it was demonstrated that perezone, a sesquiterpene quinone, is capable to induce cell death in leukemia (K562), prostate (PC-3), colorectal (HCT-15) and lung (SKLU-1) cancer cell lines; however, its mechanism of action is unknown. Therefore, in this study, in vitro and computational studies were performed to determine the mechanism of action of perezone. Firstly, changes in K562 cell viability, as well as changes in the redox status of the cell in response to treatment with several concentrations of perezone were analyzed. The type of cell death induced, and the modification of the cell cycle were determined. In addition, MD simulations and docking studies were performed to investigate the interaction of perezone with seven regulators of the apoptotic process. Finally, the ability of perezone to inhibit PARP-1 was evaluated by in vitro studies. K562 cells treated with perezone exhibited decreased viability and more oxidized status, being this effect concentration-dependent. In addition, the increase of G0/G1 phase of cell cycle and apoptosis were observed. According to the performed computational studies conducted, perezone showed the highest affinity to PARP-1 enzyme being this complex the most stable due to the presence of a small and deep cavity in the active site, which allows perezone to fit deeply by forming hydrogen bonds and hydrophobic interactions, which drive this interaction. The activity of perezone as PARP-1 inhibitor was corroborated with an IC50 = 181.5 μM. The pro-apoptotic action of perezone may be related to PARP-1 inhibition and changes in the redox state of the cell. The obtained results allowed to understand the biological effect of perezone and, consequently, these could be employed to develop novel PARP-1 inhibitors. |
| Databáze: | OpenAIRE |
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