Lysosome-dependent cell death and deregulated autophagy induced by amine-modified polystyrene nanoparticles

Nanoparticles (NPs) typically accumulate in lysosomes. However, their impact on lysosomal function, as well as autophagy, a lysosomal degradative pathway, is still not well known. We have previously reported in the 1321N1 cell line that amine-modified polystyrene (NH 2 -PS) NPs induce apoptosis through damage initiated in the lysosomes leading ultimately to release of lysosomal content in the cytosol, followed by apoptosis. Here, by using a combination of biochemical and cell biological approaches, we have characterized in a mouse embryonic fibroblast cell line that the lysosomal alterations induced by NH 2 -PS NPs is progressive, initiating from mild lysosomal membrane permeabilization (LMP), to expansion of lysosomal volume and intensive LMP before the summit of cell death. Though the cells initially seem to induce autophagy as a surviving mechanism, the damage of NH 2 -PS NPs to lysosomes probably results in lysosomal dysfunctions, leading to blockage of autophagic flux at the level of lysosomes and the eventual cell death.

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Design, Synthesis, In vitro and In silico Evaluation of New Hydrazonebased Antitumor Agents as Potent Akt Inhibitors

Letters in Drug Design & Discovery ◽

10.2174/1570180817999200618163507 ◽

2020 ◽

Vol 17 (11) ◽

pp. 1380-1392

Author(s):

Emine Merve Güngör ◽

Mehlika Dilek Altıntop ◽

Belgin Sever ◽

Gülşen Akalın Çiftçi

Keyword(s):

Cell Line ◽

Anticancer Agents ◽

In Silico ◽

Antitumor Agents ◽

Colorimetric Assay ◽

Fibroblast Cell ◽

Lipinski’S Rule ◽

In Silico Docking ◽

Embryonic Fibroblast

Background: Akt is overexpressed or activated in a variety of human cancers, including gliomas, lung, breast, ovarian, gastric and pancreatic carcinomas. Akt inhibition leads to the induction of apoptosis and inhibition of tumor growth and therefore extensive efforts have been devoted to the discovery of potent antitumor drugs targeting Akt. Objectives: The objective of this work was to identify potent anticancer agents targeting Akt. Methods: New hydrazone derivatives were synthesized and investigated for their cytotoxic effects on 5RP7 H-ras oncogene transformed rat embryonic fibroblast and L929 mouse embryonic fibroblast cell lines. Besides, the apoptotic effects of the most active compounds on 5RP7 cell line were evaluated using flow cytometry. Their Akt inhibitory effects were also investigated using a colorimetric assay. In silico docking and Absorption, Distribution, Metabolism and Excretion (ADME) studies were also performed using Schrödinger’s Maestro molecular modeling package. Results and Discussion: Compounds 3a, 3d, 3g and 3j were found to be effective on 5RP7 cells (with IC50 values of <0.97, <0.97, 1.13±0.06 and <0.97 μg/mL, respectively) when compared with cisplatin (IC50= 1.87±0.15 μg/mL). It was determined that these four compounds significantly induced apoptosis in 5RP7 cell line. Among them, N'-benzylidene-2-[(4-(4-methoxyphenyl)pyrimidin- 2-yl)thio]acetohydrazide (3g) significantly inhibited Akt (IC50= 0.5±0.08 μg/mL) when compared with GSK690693 (IC50= 0.6±0.05 μg/mL). Docking studies suggested that compound 3g showed good affinity to the active site of Akt (PDB code: 2JDO). According to in silico ADME studies, the compound also complies with Lipinski's rule of five and Jorgensen's rule of three. Conclusion: Compound 3g stands out as a potential orally bioavailable cytotoxic agent and apoptosis inducer targeting Akt.

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Cytoprotective effects of lotus (Nelumbo nucifera Gaertner) seed extracts on oxidative damaged mouse embryonic fibroblast cell

Food Science and Biotechnology ◽

10.1007/s10068-011-0212-5 ◽

2011 ◽

Vol 20 (6) ◽

pp. 1533-1537 ◽

Cited By ~ 7

Author(s):

Jihoon Sung ◽

Jung-Suk Sung ◽

Han-Seung Shin

Keyword(s):

Fibroblast Cell ◽

Mouse Embryonic Fibroblast ◽

Nelumbo Nucifera ◽

Mouse Embryonic Fibroblast Cell ◽

Embryonic Fibroblast ◽

Seed Extracts

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Cytotoxic Activity of Major Compounds from Phaleria macrocarpa (Scheff.) Boerl. Fruits

Jurnal Teknologi ◽

10.11113/jt.v64.2044 ◽

2013 ◽

Vol 64 (2) ◽

Author(s):

Siti Nur Atiqah Md Othman ◽

Norazah Basar ◽

Siti Pauliena Mohd Bohari

Keyword(s):

Cytotoxic Activity ◽

Cell Line ◽

Cell Lines ◽

Fibroblast Cell ◽

Mouse Embryonic Fibroblast ◽

Cytotoxic Activities ◽

Anticancer Properties ◽

Cervical Carcinoma Cell Line ◽

Cell Line Hela ◽

3T3 Cell Lines

P. macrocarpa is a well known Indonesian medicinal plant which is traditionally claimed to have anticancer properties. To date, there are numerous cytotoxic studies conducted on crude extracts of this plant. However, there are limited informations available regarding cytotoxic activity of the compounds isolated from this plant. Thus, this study investigated cytotoxic activity of two benzophenones derivatives identified as 2,6,4'-trihydroxy-4-methoxybenzophenone (1) and 6,4'-dihydroxy-4-methoxybenzophenone-2-O-β-D-glucopyranoside (2) isolated from the ethyl acetate extract. Cytotoxic activities of these compounds were performed against human cervical carcinoma cell line (HeLa) and mouse embryonic fibroblast cell line (3T3) using MTT assay. The result showed that benzophenone (1) exhibited low cytotoxic effect against HeLa and 3T3 cell lines with IC50 values of 132 µg/ml and 158 µg/ml, repectively while benzophenone (2) was non toxic against HeLa and 3T3 cell lines are because the IC50 is more than 250 µg/ml. These findings may sheds light on the actual properties of this plant.

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