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Cytotoxic activity of the histone deacetylase 3-Selective inhibitor Pojamide on MDA-MB-231 triple-negative breast cancer cells

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posted on 2023-06-09, 16:53 authored by Claudio Luparello, Dalia Maria Lucia Asaro, Ilenia Cruciata, Storm Hassell-HartStorm Hassell-Hart, Supojjanee Sansook, John SpencerJohn Spencer, Fabio Caradonna
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.

Funding

Poised Fragment Libraries for Atypical Bromodomain Inhibition; EPSRC-ENGINEERING & PHYSICAL SCIENCES RESEARCH COUNCIL; EP/P026990/1

History

Publication status

  • Published

File Version

  • Published version

Journal

International Journal of Molecular Sciences

ISSN

1661-6596

Publisher

MDPI

Issue

4

Volume

20

Page range

804 1-14

Department affiliated with

  • Chemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2019-02-18

First Open Access (FOA) Date

2019-02-18

First Compliant Deposit (FCD) Date

2019-02-18

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