DNA Damage Caused by Polycyclic Aromatic Hydrocarbons: Mechanisms and Markers

Muñoz, Balam; Albores, Arnulfo

doi:10.5772/22527

Cited by 33 publications

(23 citation statements)

References 61 publications

(46 reference statements)

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“…DNA adducts or ROS induced DNA damage are either repaired and/or can be converted into double strand breaks (DSBs)3942. It is thus conceivable that treatment with KPT-6566, once converted to KPT-6566-B, could induce DNA damage thus evoking a DNA damage response (DDR)43.…”

Section: Resultsmentioning

confidence: 99%

A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action

et al. 2017

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The prolyl isomerase PIN1, a critical modifier of multiple signalling pathways, is overexpressed in the majority of cancers and its activity strongly contributes to tumour initiation and progression. Inactivation of PIN1 function conversely curbs tumour growth and cancer stem cell expansion, restores chemosensitivity and blocks metastatic spread, thus providing the rationale for a therapeutic strategy based on PIN1 inhibition. Notwithstanding, potent PIN1 inhibitors are still missing from the arsenal of anti-cancer drugs. By a mechanism-based screening, we have identified a novel covalent PIN1 inhibitor, KPT-6566, able to selectively inhibit PIN1 and target it for degradation. We demonstrate that KPT-6566 covalently binds to the catalytic site of PIN1. This interaction results in the release of a quinone-mimicking drug that generates reactive oxygen species and DNA damage, inducing cell death specifically in cancer cells. Accordingly, KPT-6566 treatment impairs PIN1-dependent cancer phenotypes in vitro and growth of lung metastasis in vivo.

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Section: Resultsmentioning

confidence: 99%

A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action

et al. 2017

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“…The chemical and physical properties, such as vapor pressure and water solubility, as well as the bioaccumulation potential and toxicity of PACs, vary with the structure of PACs, including the number of rings, molecular weight, and chemical substitutions (Ravindra et al, 2008;CCME, 2010). These properties play a role in atmospheric processes of PACs, their environmental fate, and impacts on animals and human health (Boström et al, 2002;Banger et al, 2010;Diggs et al, 2011;Muñoz and Albores, 2011). The probable human PAH carcinogens according to the USEPA are benz(a)anthracene, benzo(a)pyrene, benzo(b)fluoranthene, benzo(k)fluoranthene, chrysene, dibenz(a, h)anthracene, and indeno(1, 2, 3 − cd)pyrene (ATSDR, 2008).…”

Section: Introductionmentioning

confidence: 99%

Scavenging ratios of polycyclic aromatic compounds in rain and snow in the Athabasca oil sands region

Zhang

Cheng²,

Muir

et al. 2015

Atmos. Chem. Phys.

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Abstract. The Athabasca oil sands industry in northern Alberta, Canada, is a possible source of polycyclic aromatic compounds (PACs). Monitored PACs, including polycyclic aromatic hydrocarbons (PAHs), alkylated PAHs, and dibenzothiophenes (DBTs), in precipitation and in air at three near-source sites in the Fort MacKay and Fort McMurray area during January 2011 to May 2012, were used to generate a database of scavenging ratios (Wt) for PACs scavenged by both snow and rain. Higher concentrations in precipitation and air were observed for alkylated PAHs and DBTs compared to the other PACs. The sums of the median precipitation concentrations over the period of data analyzed were 0.48 μ g L−1 for the 18 PAHs, 3.38 μ g L−1 for the 20 alkylated PAHs, and 0.94 μ g L−1 for the 5 DBTs. The sums of the median air concentrations for parent PAHs, alkylated PAHs, and DBTs were 8.37, 67.26, and 11.83 ng m−3, respectively. Median Wt over the measurement period were 6100 – 1.1 × 106 from snow scavenging and 350 – 2.3 × 105 from rain scavenging depending on the PAC species. Median Wt for parent PAHs were within the range of those observed at other urban and suburban locations, but Wt for acenaphthylene in snow samples were 2–7 times higher compared to other urban and suburban locations. Wt for some individual snow and rain samples exceeded literature values by a factor of 10. Wt for benzo(a)pyrene, dibenz(a,h)anthracene, and benzo(g,h,i)perylene in snow samples had reached 107, which is the maximum for PAH snow scavenging ratios reported in the literature. From the analysis of data subsets, Wt for particulate-phase dominant PACs were 14–20 times greater than gas-phase dominant PACs in snow samples and 7–20 times greater than gas-phase dominant PACs in rain samples. Wt from snow scavenging were ~ 9 times greater than from rain scavenging for particulate-phase dominant PACs and 4–9.6 times greater than from rain scavenging for gas-phase dominant PACs. Gas-particle fractions of each PAC, particle size distributions of particulate-phase dominant PACs, and the Henry's law constant of gas-phase dominant PACs explained, to a large extent, the different Wt values among the different PACs and precipitation types. The trend in Wt with increasing alkyl substitutions may be attributed to their physico-chemical properties, such as octanol–air and particle partition coefficients and subcooled vapor pressure, which increases gas-particle partitioning and, subsequently, the particulate mass fraction. This study verified findings from a previous study of Wang et al. (2014) that suggested that snow scavenging is more efficient than rain scavenging of particles for equivalent precipitation amounts, and also provided new knowledge of the scavenging of gas-phase PACs and alkylated PACs by snow and rain.

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“…A common feature of these four compounds is that they all require metabolic activation before causing toxicity. A number of PAH compounds are metabolised by CYP1A1 including benzopyrene and 2-(acetylamino)fluorine (Muñoz and Albores, 2011). The expression of several genes required for detoxification and metabolic activation, GST2A, GADD α and CYP1A1, was confirmed in the HEPG2 cell line (data not shown).…”

Section: Q-pcr Compound Designation Compound Namementioning

confidence: 92%

Quantitative analysis of gene expression changes in response to genotoxic compounds

Morris

El‐Hiti

Weeks

et al. 2017

Toxicology in Vitro

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Techniques that quantify molecular endpoints sufficiently sensitive to identify and classify potentially toxic compounds have wide potential for high-throughput in vitro screening. Expression of three genes, RAD51C, TP53 and cystatin A (CSTA), in HEPG2 cells was measured by Q-PCR amplification. In parallel, we developed alternative assays for the same 3 gene signature based on an acridinium-ester chemiluminescent reporter molecule. HEPG2 cells were challenged with eighteen different compounds (n=18) chosen to represent compounds that are genotoxic (n=8), non-genotoxic non-carcinogenic (n=2) or have a less well defined mechanism of action with respect to genotoxicity (n=8). At least one of the three genes displayed dysregulated expression in the majority of compounds tested by Q-PCR and ten compounds changed the CSTA expression significantly. Acridinium-ester labelled probes for the three genes were synthesised and tested. Analytical sensitivity was characterised and suggested a limit of detection generally better than 0.1fmol but often 10-50 attomol. A linear amplification step was optimised and this quantitative method detected statistically significant increases in RAD51C and CSTA expression in agreement with the Q-PCR results, demonstrating the potential of this technology. The broad agreement of the amplified chemiluminescent method and Q-PCR in measuring gene expression suggests wider potential application for this chemiluminescent technology.

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DNA Damage Caused by Polycyclic Aromatic Hydrocarbons: Mechanisms and Markers

Cited by 33 publications

References 61 publications

A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action

A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action

Scavenging ratios of polycyclic aromatic compounds in rain and snow in the Athabasca oil sands region

Quantitative analysis of gene expression changes in response to genotoxic compounds

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