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Cytotoxic Activity of the Histone Deacetylase 3-Selective Inhibitor Pojamide on MDA-MB-231 Triple-Negative Breast Cancer Cells

1
Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università di Palermo, Viale delle Scienze, 90128 Palermo, Italy
2
Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QJ, UK
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(4), 804; https://doi.org/10.3390/ijms20040804
Received: 7 January 2019 / Revised: 2 February 2019 / Accepted: 6 February 2019 / Published: 13 February 2019
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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Abstract

We examined the effects of the ferrocene-based histone deacetylase-3 inhibitor Pojamide (N1-(2-aminophenyl)-N8-ferrocenyloctanediamide) and its two derivatives N1-(2-aminophenyl)-N6-ferrocenyladipamide and N1-(2-aminophenyl)-N8-ferroceniumoctanediamide tetrafluoroborate on triple-negative MDA-MB-231 breast cancer cells. Viability/growth assays indicated that only the first two compounds at 70 μM concentration caused an approximate halving of cell number after 24 h of exposure, whereas the tetrafluoroborate derivative exerted no effect on cell survival nor proliferation. Flow cytometric and protein blot analyses were performed on cells exposed to both Pojamide and the ferrocenyladipamide derivative to evaluate cell cycle distribution, apoptosis/autophagy modulation, and mitochondrial metabolic state in order to assess the cellular basis of the cytotoxic effect. The data obtained show that the cytotoxic effect of the two deacetylase inhibitors may be ascribed to the onset of non-apoptotic cell death conceivably linked to a down-regulation of autophagic processes and an impairment of mitochondrial function with an increase in intracellular reactive oxygen species. Our work expands the list of autophagy-regulating drugs and also provides a further example of the role played by the inhibition of autophagy in breast cancer cell death. Moreover, the compounds studied may represent attractive and promising targets for subsequent molecular modeling for anti-neoplastic agents in malignant breast cancer. View Full-Text
Keywords: histone deacetylase inhibitor; breast cancer cells; cell viability; cell cycle; apoptosis; autophagy; reactive oxygen species; mitochondrial transmembrane potential histone deacetylase inhibitor; breast cancer cells; cell viability; cell cycle; apoptosis; autophagy; reactive oxygen species; mitochondrial transmembrane potential
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Luparello, C.; Asaro, D.M.L.; Cruciata, I.; Hassell-Hart, S.; Sansook, S.; Spencer, J.; Caradonna, F. Cytotoxic Activity of the Histone Deacetylase 3-Selective Inhibitor Pojamide on MDA-MB-231 Triple-Negative Breast Cancer Cells. Int. J. Mol. Sci. 2019, 20, 804.

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