Selective Cytotoxic Activity and DNA Damage by an Epoxyalkyl Galactopyranoside

2018 ◽  
Author(s):  
Estefanía Burgos-Morón ◽  
Nuria Pastor ◽  
Manuel Luis Orta ◽  
Julio José Jiménez-Alonso ◽  
Margarita Vega-Holm ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Anticancer Activity ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Excision Repair ◽  
Lactate Production ◽  
Glucose Consumption ◽  
Lung Cancer Cells ◽  
Normal Cells

Several clinically useful anticancer drugs selectively kill cancer cells by inducing DNA damage; the genomic instability and DNA repair defects of cancer cells make them more vulnerable than normal cells to the cytotoxicity of DNA-damaging agents. Because epoxide-containing compounds can induce DNA damage, we have used the MTT assay to evaluate the selective cytotoxicity of three epoxyalkyl galactopyranosides against A549 lung cancer cells and MRC-5 lung normal cells. Compound (2S,3S)-2,3-Epoxydecyl 4,6-O-(S)-benzylidene-β-D-galactopyranoside (EDBGP) showed the highest selective anticancer activity and was selected for mechanistic studies. After observing that EDBGP induced cellular DNA damage (comet assay), we found that cells deficient in nucleotide excision repair were hypersensitive to the cytotoxicity of this compound; this suggests that EDBGP may induce bulky DNA adducts. EDBGP did not inhibit glycolysis (glucose consumption and lactate production). Pre-treatment of lung cancer cells with several antioxidants did not reduce the cytotoxicity of EDBGP, thereby indicating that reactive oxygen species do not participate in the anticancer activity of this compound. Finally, EDBGP was screened against a panel of cancer cells and normal cells from several tissues, including three genetically modified skin fibroblasts with increasing degree of malignancy. Our results suggest that epoxyalkyl galactopyranosides are promising lead compounds for the development of new anticancer agents.

scholarly journals Screening for Selective Anticancer Activity of 65 Extracts of Plants Collected in Western Andalusia, Spain

2018 ◽  
Author(s):  
José Manuel Calderón-Montaño ◽  
Sara María Martínez-Sánchez ◽  
Estefanía Burgos-Morón ◽  
Emilio Guillén-Mancina ◽  
Julio José Jiménez-Alonso ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cytotoxic Activity ◽  
Anticancer Activity ◽  
Cancer Cells ◽  
Cell Lines ◽  
Selectivity Index ◽  
Lung Cancer Cells ◽  
Taxus Baccata ◽  
Normal Cells ◽  
Tetraclinis Articulata

In our continuous search for selective anticancer treatments, we have screened 65 extracts from 45 plants collected in several areas of Western Andalusia (Spain) for cytotoxic activity against lung cancer cells and lung normal cells. Active extracts were also tested against 11 cell lines from other tissues. An extract from the leaves of Tetraclinis articulata (Vahl) Mast. (Cupressaceae) showed a marked cytotoxicity (IC50 = 0.37 ± 0.03 µg/mL) and selectivity (selectivity index = 378.3) against the lung cancer cells; cisplatin, 5-fluorouracil and an extract from the leaves of Taxus baccata L. (Taxaceae) were less cytotoxic and selective.

scholarly journals Nuclear Transglutaminase 2 interacts with topoisomerase II⍺ to promote DNA damage repair in lung cancer cells

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Xiao Lei ◽  
Kun Cao ◽  
Yuanyuan Chen ◽  
Hui Shen ◽  
Zhe Liu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Cancer Therapy ◽  
Cancer Cells ◽  
Protein Localization ◽  
Transglutaminase 2 ◽  
Lung Cancer Cells ◽  
Mass Spectrometry Analysis ◽  
Cancer Resistance ◽  
Dsb Repair

Abstract Background To block repairs of DNA damages, especially the DNA double strand break (DSB) repair, can be used to induce cancer cell death. DSB repair depends on a sequential activation of DNA repair factors that may be potentially targeted for clinical cancer therapy. Up to now, many protein components of DSB repair complex remain unclear or poorly characterized. In this study, we discovered that Transglutaminase 2 (TG2) acted as a new component of DSB repair complex. Methods A bioinformatic analysis was performed to identify DNA damage relative genes from dataset from The Cancer Genome Atlas. Immunofluorescence and confocal microscopy were used to monitor the protein localization and recruitment kinetics. Furthermore, immunoprecipitation and mass spectrometry analysis were performed to determine protein interaction of both full-length and fragments or mutants in distinct domain. In situ lung cancer model was used to study the effects cancer therapy in vivo. Results After DSB induction, cytoplasmic TG2 was extensively mobilized and translocated into nucleus after phosphorylated at T162 site by DNA-PKcs. Nuclear TG2 quickly accumulated at DSB sites and directly interacting with Topoisomerase IIα (TOPOIIα) with its TGase domain to promote DSB repair. TG2 deficient cells lost capacity of DSB repair and become susceptible to ionizing radiation. Specific inhibition of TG2-TOPOIIα interaction by glucosamine also significantly inhibited DSB repair, which increased sensitivity in lung cancer cells and engrafted lung cancers. Conclusions These findings elucidate new mechanism of TG2 in DSB repair trough directly interacting with TOPOIIα, inhibition of which provided potential target for overcoming cancer resistance.

scholarly journals Suppression of Sirt1 sensitizes lung cancer cells to WEE1 inhibitor MK-1775-induced DNA damage and apoptosis

Oncogene ◽  
2017 ◽  
Vol 36 (50) ◽  
pp. 6863-6872 ◽  
Author(s):  
G Chen ◽  
B Zhang ◽  
H Xu ◽  
Y Sun ◽  
Y Shi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Lung Cancer Cells

scholarly journals CSB affected on the sensitivity of lung cancer cells to platinum-based drugs through the global decrease of let-7 and miR-29

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Zhenbang Yang ◽  
Chunling Liu ◽  
Hongjiao Wu ◽  
Yuning Xie ◽  
Hui Gao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Excision Repair ◽  
Lung Cancer Cells ◽  
Luciferase Reporter ◽  
Luciferase Reporter Gene ◽  
Platinum Based Chemotherapy ◽  
Reporter Gene Analysis ◽  
Induced Apoptosis ◽  
Syndrome Protein

Abstract Background Transcription-coupled nucleotide excision repair (TC-NER) plays a prominent role in the removal of DNA adducts induced by platinum-based chemotherapy reagents. Cockayne syndrome protein B (CSB), the master sensor of TCR, is also involved in the platinum resistant. Let-7 and miR-29 binding sites are highly conserved in the proximal 3′UTR of CSB. Methods We conducted immunohistochemisty to examine the expression of CSB in NSCLC. To determine whether let-7 family and miR-29 family directly interact with the putative target sites in the 3′UTR of CSB, we used luciferase reporter gene analysis. To detect the sensitivity of non-small cell lung cancer (NSCLC) cells to platinum-based drugs, CCK analysis and apoptosis analysis were performed. Results We found that let-7 and miR-29 negatively regulate the expression of CSB by directly targeting to the 3′UTR of CSB. The endogenous CSB expression could be suppressed by let-7 and miR-29 in lung cancer cells. The suppression of CSB activity by endogenous let-7 and miR-29 can be robustly reversed by their sponges. Down-regulation of CSB induced apoptosis and increased the sensitivity of NSCLC cells to cisplatin and carboplatin drugs. Let-7 and miR-29 directly effect on cisplatin and carboplatin sensitivity in NSCLC. Conclusions In conclusion, the platinum-based drug resistant of lung cancer cells may involve in the regulation of let-7 and miR-29 to CSB.

scholarly journals Myrcene Exhibits Antitumor Activity Against Lung Cancer Cells by Inducing Oxidative Stress and Apoptosis Mechanisms

2020 ◽  
Vol 15 (9) ◽  
pp. 1934578X2096118
Author(s):  
Xudong Bai ◽  
Jin Tang
Keyword(s):  
Oxidative Stress ◽  
Lung Cancer ◽  
Dna Damage ◽  
Cell Death ◽  
Cancer Cells ◽  
Metabolic Activity ◽  
Lung Cancer Cells ◽  
Adenocarcinoma Cells ◽  
Lung Adenocarcinoma Cells ◽  
A549 Lung

Myrcene, a natural olefinic hydrocarbon, possesses anti-inflammatory, analgesic, antibiotic, and antimutagenic properties, but its anticancer effect has not yet been elucidated. Hence, the present study was framed to investigate the molecular mechanism by which myrcene mediates the anticancer activity of A549 lung adenocarcinoma cells. In vitro, A549 lung cancer cells were cultured either with or without myrcene, and the effects on cellular metabolic activity, levels of reactive oxygen species (ROS), mitochondrial integrity, deoxyribonucleic acid (DNA) damage, and activity of caspases were analyzed. The study demonstrated that compared with control cells, myrcene induces cell death in a dose-dependent manner while inducing ROS levels. Further experiments revealed that the metabolic activity of the A549 lung adenocarcinoma cells was diminished with increased DNA damage and altered cellular integrity. In addition, increased activity of caspase-3 was also evidenced with reduced mitochondrial membrane potential synthesis in the myrcene-treated cells, which demonstrate that lung cancer cells experience signs of toxicity during myrcene treatment through the activation of the apoptosis mechanism via mitochondria-mediated cell death signaling and induction of oxidative stress. The results provide the first report on the evidence of anticancer activity and the possibility of a new drug that could be used for the treatment of lung cancer.

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