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.
Highlights
Genotoxicity, as defined by toxicological genetics and mutagenesis, describes the ability of chemical agents to induce modifications to the DNA nucleotide sequence or double helix structure of an organism, damaging its genetic information, thereby causing mutations that can lead to the onset of cancer [1]
This result prompted us to examine the toxicity of this specific molecule from different angles by probing its endocellular/endonuclear and epigenetic action, because carbazole derivatives have been reported as non-toxic mainly when tested at the molecular level, but highly genotoxic when submitted to other tests, including the Comet assay [12]
Variations and DNA methylation at the gene level, overall our data show that small modifications in the substitution patterns of carbazoles can have profound effects on their intrinsic genotoxic and epigenetic properties, which may be exploited for their use as anticancer agents and probe molecules
Summary
Genotoxicity, as defined by toxicological genetics and mutagenesis, describes the ability of chemical agents to induce modifications to the DNA nucleotide sequence or double helix structure of an organism, damaging its genetic information, thereby causing mutations that can lead to the onset of cancer [1]. Carbazoles have been shown to induce against a wide spectrum of diseases, including cancer, microbial infections and neurological epigenetic anomalies, such as changes in DNA methylation status, and to exert gendisorders [4,5,6]. Exposure to mahanine, a carbazole alkaloid from such as changes in DNA methylation status, and to exert genotoxic effects. 2) gene promoter and its has been acknowledged The former molecule was proven to potentiate demethylate expression, resulting in deficient angiogenesis by endothelial cells. PK9320 and PK9323, which bound mutant led to second-generation analogues, PK9320 and PK9323, whichthe bound the with higher wereand more potent stabilizing and reactivating the mutant mutant withaffinity higherand affinity were moreinpotent in stabilizing and reactivating thethan muthe compound (Figure 1) Those second-generation carbazoles restored tantparent than the parent compound (Figure 1).
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