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Mechanism of antiproliferative effect of primaquine-cinnamic acid derivatives on MCF-7 adenocarcinoma cell line

In our previous paper we have described synthesis and biological evaluation of novel primaquine-cinnamic acid derivatives (PQ-CAD) of the amide and acylsemicarbazide type. The results showed that the title compounds possess strong antiproliferative activity against a number of tested cancer cell lines or selectivity towards human breast adenocarcinoma cell line (MCF-7) [1]. Among all tested compounds, three derivatives especially attracted our attention: (E)-3-(2-fluorophenyl)-N-(4-(6-methoxyquinolin-8-ylamino)pentyl)acrylamide (1), (E)-1-(3-(4-methoxyphenyl)acryloyl)-4-(4-(6-methoxyquinolin-8-ylamino)pentyl)semicarbazide (2) and (E)-4-(4-(6-methoxyquinolin-8-ylamino)pentyl)-1-(3-(4-(trifluoromethyl)phenyl) acryloyl)semicarbazide (3) as they exhibited strong and/or selective antiproliferative activity towards MCF-7 cell line. In order to elucidate mechanisms of action of the selected PQ-CAD derivatives on the MCF-7 cell line, morphology, caspase activity, levels of the apoptosis proteins, cell invasion and migration were studied following exposure of MCF-7 cells to the test compounds. Morphological studies of the effects of the tested compounds on MCF-7 cells, conducted using hematoxylin and eosin stain, revealed that compounds 1 and 3 induced morphological changes in MCF-7 cells characteristic of apoptosis. Compounds 1 and 3 also showed significant effects on the proteins that modulate apoptosis as they induced PARP cleavage, elevation of Bad protein level, p53 phosphorylation and caspase-9 activation. Additionally, compounds 1 and 3 inhibited MCF-7 migration and invasion. On the other hand, morphological studies of 2-treated cells suggested that MCF-7 cells were mainly in interphase and compound 2 only marginally decreased cell migration and invasion. Taking into account all the above mentioned facts, it can be concluded that compounds 1 and 3 inhibited MCF-7 cell growth by inducing apoptotic cell death, while compound 2 controlled the cell circle by different mechanisms.

primaquine, cinnamic acid derivatives, antiproliferative effect, MCF-7 cell line

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