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Article

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

1
Department of Biological Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Viale delle Scienze, Edificio 16, 90128 Palermo, Italy
2
Institute of Pharmaceutical Chemistry, Goethe University, 60438 Frankfurt am Main, Germany
3
Buchmann Institute for Molecular Life Sciences, Structural Genomics Consortium (SGC), 60438 Frankfurt am Main, Germany
4
Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QJ, UK
5
Eurofins Integrated Discovery UK Ltd., Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, UK
*
Authors to whom correspondence should be addressed.
Current address: The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
Academic Editor: Daniela Trisciuoglio
Int. J. Mol. Sci. 2021, 22(7), 3410; https://doi.org/10.3390/ijms22073410
Received: 1 March 2021 / Revised: 22 March 2021 / Accepted: 23 March 2021 / Published: 26 March 2021
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. View Full-Text
Keywords: genomic instability; carbazole derivatives; epigenetics; DNA methylation; breast cancer genomic instability; carbazole derivatives; epigenetics; DNA methylation; breast cancer
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MDPI and ACS Style

Luparello, C.; Cruciata, I.; Joerger, A.C.; Ocasio, C.A.; Jones, R.; Tareque, R.K.; Bagley, M.C.; Spencer, J.; Walker, M.; Austin, C.; Ferrara, T.; D′Oca, P.; Bellina, R.; Branni, R.; Caradonna, F. Genotoxicity and Epigenotoxicity of Carbazole-Derived Molecules on MCF-7 Breast Cancer Cells. Int. J. Mol. Sci. 2021, 22, 3410. https://doi.org/10.3390/ijms22073410

AMA Style

Luparello C, Cruciata I, Joerger AC, Ocasio CA, Jones R, Tareque RK, Bagley MC, Spencer J, Walker M, Austin C, Ferrara T, D′Oca P, Bellina R, Branni R, Caradonna F. Genotoxicity and Epigenotoxicity of Carbazole-Derived Molecules on MCF-7 Breast Cancer Cells. International Journal of Molecular Sciences. 2021; 22(7):3410. https://doi.org/10.3390/ijms22073410

Chicago/Turabian Style

Luparello, Claudio, Ilenia Cruciata, Andreas C. Joerger, Cory A. Ocasio, Rhiannon Jones, Raysa K. Tareque, Mark C. Bagley, John Spencer, Martin Walker, Carol Austin, Tiziana Ferrara, Pietro D′Oca, Rossella Bellina, Rossella Branni, and Fabio Caradonna. 2021. "Genotoxicity and Epigenotoxicity of Carbazole-Derived Molecules on MCF-7 Breast Cancer Cells" International Journal of Molecular Sciences 22, no. 7: 3410. https://doi.org/10.3390/ijms22073410

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