ijms-carbazole tox claudio.pdf (1.59 MB)
Genotoxicity and epigenotoxicity of carbazole-derived molecules on mcf-7 breast cancer cells
journal contribution
posted on 2023-06-09, 23:33 authored by Claudio Luparello, Ilenia Cruciata, Andreas C Joerger, Cory A Ocasio, Rhiannon Jones, Raysa Khan, Mark BagleyMark Bagley, John SpencerJohn Spencer, Martin Walker, Carol Austin, Tiziana Ferrara, Pietro D'Oca, Rossella Bellina, Rossella Branni, Fabio CaradonnaThe 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-?H2AX histone, Comet assay and methylation-sensitive arbitrarily primed PCR to analyze their intrinsic DNA damageinducing 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.
Funding
Rescuing p53 Function in Cancer. Targeting the Y220C Mutation; G2344; WORLDWIDE CANCER RESEARCH; 18-0043
History
Publication status
- Published
File Version
- Published version
Journal
International Journal of Molecular SciencesISSN
1661-6596Publisher
MDPIExternal DOI
Issue
7Volume
22Page range
1-14Article number
a3410Department affiliated with
- Chemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2021-04-12First Open Access (FOA) Date
2021-04-12First Compliant Deposit (FCD) Date
2021-04-11Usage metrics
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