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Open Access 01-12-2018 | PRECLINICAL STUDIES

The molecular mechanism of anticancer action of novel octahydropyrazino[2,1-a:5,4-a′]diisoquinoline derivatives in human gastric cancer cells

Authors: Natalia Pawłowska, Agnieszka Gornowicz, Anna Bielawska, Arkadiusz Surażyński, Anna Szymanowska, Robert Czarnomysy, Krzysztof Bielawski

Published in: Investigational New Drugs | Issue 6/2018

Summary

Objective The aim of the current study was to examine the anticancer activity and the detailed mechanism of novel diisoquinoline derivatives in human gastric cancer cells (AGS). Methods The viability of AGS cells was measured by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Cell cycle analysis and apoptosis assay were performed by standard flow cytometric method. Confocal microscopy bioimaging was used to demonstrate the expression of pivotal proteins engaged in apoptosis (caspase-8, caspase-3, p53) and cell signaling (AKT, ERK1/2). Results All compounds decreased the number of viable cells in a dose-dependent manner after 24 and 48 h of incubation, although compound 2 was a more cytotoxic agent, with IC₅₀ values of 21 ± 2 and 6 ± 2 μM, compared to 80 ± 2 and 45 ± 2 μM for etoposide. The cytotoxic and antiproliferative effects of novel compounds were associated with the induction of apoptosis. The highest percentage of early and late apoptotic cells was observed after 48 h of incubation with compound 2 (89.9%). The value was higher compared to compound 1 (20.4%) and etoposide (24.1%). The novel diisoquinoline derivatives decreased the expression of AKT and ERK1/2. Their mechanism was associated with p53-mediated apoptosis, accumulation of cells in the G2/M phase of cell cycle and inhibition of topoisomerase II. Conclusion These data strongly support compound 2 as a promising molecule for treatment of gastric cancer.

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Title: The molecular mechanism of anticancer action of novel octahydropyrazino[2,1-a:5,4-a′]diisoquinoline derivatives in human gastric cancer cells
Authors: Natalia Pawłowska
Agnieszka Gornowicz
Anna Bielawska
Arkadiusz Surażyński
Anna Szymanowska
Robert Czarnomysy
Krzysztof Bielawski
Publication date: 01-12-2018
Publisher: Springer US
Published in: Investigational New Drugs / Issue 6/2018
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-018-0584-y

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