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Genotoxicity and Epigenotoxicity of Carbazole-Derived Molecules on MCF-7 Breast Cancer Cells

Genotoxicity and Epigenotoxicity of Carbazole-Derived Molecules on MCF-7 Breast Cancer Cells

Authors :
Andreas C. Joerger
Rossella Branni
Ilenia Cruciata
Fabio Caradonna
Raysa Khan Tareque
Rossella Bellina
Carol Austin
Cory A. Ocasio
Pietro D Oca
Tiziana Ferrara
Martin Walker
Mark C. Bagley
Claudio Luparello
Rhiannon N. Jones
John Spencer
Luparello, Claudio
Cruciata, Ilenia
Joerger, Andreas C.
Ocasio, Cory A.
Jones, Rhiannon
Tareque, Raysa Khan
Bagley, Mark C.
Spencer, John
Walker, Martin
Austin, Carol
Ferrara, Tiziana
D′Oca, Pietro
Bellina, Rossella
Branni, Rossella
Caradonna, Fabio
Source :
International Journal of Molecular Sciences, Vol 22, Iss 3410, p 3410 (2021), International Journal of Molecular Sciences, Volume 22, Issue 7
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

The carbazole compounds PK9320 (1-(9-ethyl-7-(furan-2-yl)-9H-carbazol-3-yl)-N-methylmethanamine) and PK9323 (1-(9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)-N-methylmethanamine), second-generation analogues of PK083 (1-(9-ethyl-9H-carbazol-3-yl)-N-methylmethanamine), restore p53 signaling in Y220C p53-mutated cancer cells by binding to a mutation-induced surface crevice and acting as molecular chaperones. In the present paper, these three molecules have been tested for mutant p53-independent genotoxic and epigenomic effects on wild-type p53 MCF-7 breast adenocarcinoma cells, employing a combination of Western blot for phospho-γH2AX histone, Comet assay and methylation-sensitive arbitrarily primed PCR to analyze their intrinsic DNA damage-inducing and DNA methylation-changing abilities. We demonstrate that small modifications in the substitution patterns of carbazoles can have profound effects on their intrinsic genotoxic and epigenetic properties, with PK9320 and PK9323 being eligible candidates as “anticancer compounds” and “anticancer epi-compounds” and PK083 a “damage-corrective” compound on human breast adenocarcinoma cells. Such different properties may be exploited for their use as anticancer agents and chemical probes.

Details

ISSN :
14220067 and 16616596
Volume :
22
Database :
OpenAIRE
Journal :
International Journal of Molecular Sciences
Accession number :
edsair.doi.dedup.....42d31c6f019e685c32e3146ea342d8ef
Full Text :
https://doi.org/10.3390/ijms22073410