scholarly journals In Vitro Assessment of the Genotoxic Hazard of Novel Hydroxamic Acid- and Benzamide-Type Histone Deacetylase Inhibitors (HDACi)

2020 ◽  
Vol 21 (13) ◽  
pp. 4747
Author(s):  
Annabelle Friedrich ◽  
Ann-Sophie Assmann ◽  
Lena Schumacher ◽  
Jana v. Stuijvenberg ◽  
Matthias U. Kassack ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Hydroxamic Acid ◽  
Histone Deacetylase Inhibitors ◽  
Excision Repair ◽  
Strand Break ◽  
In Vivo Studies ◽  
Therapeutic Window ◽  
V79 Cells

Histone deacetylase inhibitors (HDACi) are already approved for the therapy of leukemias. Since they are also emerging candidate compounds for the treatment of non-malignant diseases, HDACi with a wide therapeutic window and low hazard potential are desirable. Here, we investigated a panel of 12 novel hydroxamic acid- and benzamide-type HDACi employing non-malignant V79 hamster cells as toxicology guideline-conform in vitro model. HDACi causing a ≥10-fold preferential cytotoxicity in malignant neuroblastoma over non-malignant V79 cells were selected for further genotoxic hazard analysis, including vorinostat and entinostat for control. All HDACi selected, (i.e., KSK64, TOK77, DDK137 and MPK77) were clastogenic and evoked DNA strand breaks in non-malignant V79 cells as demonstrated by micronucleus and comet assays, histone H2AX foci formation analyses (γH2AX), DNA damage response (DDR) assays as well as employing DNA double-strand break (DSB) repair-defective VC8 hamster cells. Genetic instability induced by hydroxamic acid-type HDACi seems to be independent of bulky DNA adduct formation as concluded from the analysis of nucleotide excision repair (NER) deficient mutants. Summarizing, KSK64 revealed the highest genotoxic hazard and DDR stimulating potential, while TOK77 and MPK77 showed the lowest DNA damaging capacity. Therefore, these compounds are suggested as the most promising novel candidate HDACi for subsequent pre-clinical in vivo studies.

Histone Deacetylase Inhibitors: Assays to Assess Effectiveness In Vitro and In Vivo

2003 ◽  
pp. 199-205 ◽  
Author(s):  
Victoria M Richon ◽  
Xianbo Zhou ◽  
J.Paul Secrist ◽  
Carlos Cordon-Cardo ◽  
W.Kevin Kelly ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors

scholarly journals ERCC1-XPF Endonuclease Facilitates DNA Double-Strand Break Repair

2008 ◽  
Vol 28 (16) ◽  
pp. 5082-5092 ◽  
Author(s):  
Anwaar Ahmad ◽  
Andria Rasile Robinson ◽  
Anette Duensing ◽  
Ellen van Drunen ◽  
H. Berna Beverloo ◽  
...  
Keyword(s):  
Gamma Irradiation ◽  
Excision Repair ◽  
Strand Break ◽  
Dna Lesions ◽  
End Joining ◽  
Dsb Repair ◽  
Large Deletions ◽  
Mutant Cells

ABSTRACT ERCC1-XPF endonuclease is required for nucleotide excision repair (NER) of helix-distorting DNA lesions. However, mutations in ERCC1 or XPF in humans or mice cause a more severe phenotype than absence of NER, prompting a search for novel repair activities of the nuclease. In Saccharomyces cerevisiae, orthologs of ERCC1-XPF (Rad10-Rad1) participate in the repair of double-strand breaks (DSBs). Rad10-Rad1 contributes to two error-prone DSB repair pathways: microhomology-mediated end joining (a Ku86-independent mechanism) and single-strand annealing. To determine if ERCC1-XPF participates in DSB repair in mammals, mutant cells and mice were screened for sensitivity to gamma irradiation. ERCC1-XPF-deficient fibroblasts were hypersensitive to gamma irradiation, and γH2AX foci, a marker of DSBs, persisted in irradiated mutant cells, consistent with a defect in DSB repair. Mutant mice were also hypersensitive to irradiation, establishing an essential role for ERCC1-XPF in protecting against DSBs in vivo. Mice defective in both ERCC1-XPF and Ku86 were not viable. However, Ercc1 −/− Ku86 −/− fibroblasts were hypersensitive to gamma irradiation compared to single mutants and accumulated significantly greater chromosomal aberrations. Finally, in vitro repair of DSBs with 3′ overhangs led to large deletions in the absence of ERCC1-XPF. These data support the conclusion that, as in yeast, ERCC1-XPF facilitates DSB repair via an end-joining mechanism that is Ku86 independent.

scholarly journals Histone Deacetylase Inhibitors with Enhanced Enzymatic Inhibition Effects and Potent in vitro and in vivo Antitumor Activities

ChemMedChem ◽  
2013 ◽  
Vol 9 (3) ◽  
pp. 638-648 ◽  
Author(s):  
Lei Zhang ◽  
Yingjie Zhang ◽  
C. James Chou ◽  
Elizabeth S. Inks ◽  
Xuejian Wang ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Antitumor Activities ◽  
Enzymatic Inhibition

Supremacy of Synergism: A comparison of anticancer activity of Rhizome Extract of Bistorta amplexicualis and gallic acid in Cancer Cell Lines and Primary Cells

2020 ◽  
Vol 01 ◽  
Author(s):  
Salma Batool ◽  
M. Javaid Asad ◽  
Muhammad Arshad ◽  
Rahman Shah Zaib Saleem ◽  
Muhammad Sheeraz Ahmad
Keyword(s):  
Gallic Acid ◽  
Cell Line ◽  
Cancer Cell ◽  
Plant Extract ◽  
Umbilical Vein ◽  
Cancer Cell Line ◽  
In Vivo Studies ◽  
Therapeutic Window

Background: Bistorta amplexicaulis is a seasonal herb with several folkloric uses. The plant extract has been shown to possess various activities including antioxidant, anticancer, anti-bacterial, anti-fungal, cardio-protective, anti-atherosclerosis activities. Objective: The aim of the study was to quantify the activity of the plant extract and relate it to the activity of the isolated compounds, gallic acid. Methods: Extraction of the plant was carried out. Then the activity of the extract was compared with its constituent, gallic acid. Cytotoxic potential of the two against human liver cancer cell line (HepG2), breast cancer cell line (MCF-7) and human umbilical vein endothelial cells (HUVEC) was evaluated through MTS assay. Results: The extract had better activity against HepG2 as compared to gallic acid (IC50 29µg/mL vs 37µg/mL). It also provided a better therapeutic window by having lower toxicity for HUVEC cells than gallic acid (IC50 63µg/mL vs 47µg/mL) suggesting the use of the extract over the purified gallic acid for these cells. We also performed the fluorescence study of the rhizome extract in ethanol (REE), methanol (REM), 80% ethanol (80RE), 80% methanol, (80RM) and acetone (RAC). The highest intensity of fluorescence was found in REE with excitation at 394 nm and emission at 421nm. Conclusion: The comparison of gallic acid with ethanolic rhizome extract of B. amplexicaulis reveals important insights about utilizing the plant extract over purified gallic acid. The ethanolic extract also has the potential to be used as autoflouresent drug during in vitro and in vivo studies.

Neutrophils inhibit pulmonary nucleotide excision repair: Evidence from in vitro and in vivo studies

2007 ◽  
Vol 169 (2) ◽  
pp. 134
Author(s):  
N. Güngör ◽  
R.W.L. Godschalk ◽  
D. Pachen ◽  
A. Haegens ◽  
F.J. Van Schooten ◽  
...  
Keyword(s):  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
In Vivo Studies ◽  
Nucleotide Excision
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