scholarly journals KEAP1 Is Required for Artesunate Anticancer Activity in Non-Small-Cell Lung Cancer

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1885
Author(s):  
Kristen S. Hill ◽  
Anthony McDowell ◽  
J. Robert McCorkle ◽  
Erin Schuler ◽  
Sally R. Ellingson ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Cellular Response ◽  
A549 Cells ◽  
Small Cell ◽  
Related Factor ◽  
Small Cell Lung ◽  
Lung Cancers ◽  
Nrf2 Pathway ◽  
Inactivating Mutation ◽  
Further Development

Artesunate is the most common treatment for malaria throughout the world. Artesunate has anticancer activity likely through the induction of reactive oxygen species, the same mechanism of action utilized in Plasmodium falciparum infections. Components of the kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway, which regulates cellular response to oxidative stress, are mutated in approximately 30% of non-small-cell lung cancers (NSCLC); therefore, we tested the hypothesis that KEAP1 is required for artesunate sensitivity in NSCLC. Dose response assays identified A549 cells, which have a G333C-inactivating mutation in KEAP1, as resistant to artesunate, with an IC50 of 23.6 µM, while H1299 and H1563 cells were sensitive to artesunate, with a 10-fold lower IC50. Knockdown of KEAP1 through siRNA caused increased resistance to artesunate in H1299 cells. Alternatively, the pharmacological inhibition of NRF2, which is activated downstream of KEAP1 loss, by ML385 partially restored sensitivity of A549 cells to artesunate, and the combination of artesunate and ML385 was synergistic in both A549 and H1299 cells. These findings demonstrate that KEAP1 is required for the anticancer activity of artesunate and support the further development of NRF2 inhibitors to target patients with mutations in the KEAP1/NRF2 pathway.

scholarly journals Silencing miR-21 Sensitizes Non-Small Cell Lung Cancer A549 Cells to Ionizing Radiation through Inhibition of PI3K/Akt

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Yongfu Ma ◽  
Hui Xia ◽  
Yang Liu ◽  
Min Li
Keyword(s):  
Ionizing Radiation ◽  
Protein Level ◽  
A549 Cells ◽  
Clonogenic Survival ◽  
Negative Control ◽  
Small Cell ◽  
Small Cell Lung ◽  
Lung Cancers ◽  
Phosphorylated Akt

We investigated the role of microRNA-21 (miR-21) in radiotherapy resistance of non-small cell lung cancers (NSCLC) and the underlying molecular mechanism. A549 cells were transfected with anti-miR-21 or the negative control oligonucleotides and real-time PCR was applied to detect miR-21 expression level. After ionizing radiation (IR), the survival fractions, proliferation, apoptosis, and expression of phosphorylated-Akt of A549 cells were determined by clonogenic survival analysis, MTT assay, flow cytometry, and Western blotting. Downregulation of miR-21 in radioresistant NSCLC A549 cells inhibited the colony-forming ability and proliferation of A549 cells after IR. Moreover, silencing miR-21 enhanced apoptosis of A549 cells induced by IR accompanied by decreased phosphorylated-Akt protein level. However, PI3K activator IGF-1 reversed suppression of phosphorylated-Akt protein level and promotion of apoptosis of A549 cells after IR caused by miR-21 knockdown. Silencing miR-21 in radioresistant NSCLC A549 cells sensitized them to IR by inhibiting cell proliferation and enhancing cell apoptosis through inhibition of PI3K/Akt signaling pathway. This might help in sensitization of NSCLC to radiotherapy.

scholarly journals Lidocaine Inhibited Migration of Non-Small-Cell Lung Cancer A549 Cells via the CXCR4 Regulation

2021 ◽  
Author(s):  
Baichun Xing ◽  
Linlin Yang ◽  
Yanan Cui
Keyword(s):  
Wound Healing ◽  
Cell Death ◽  
Cell Viability ◽  
Plasma Concentrations ◽  
A549 Cells ◽  
Small Cell ◽  
Filamentous Actin ◽  
Small Cell Lung ◽  
Lung Cancers ◽  
Intracellular Ca

Abstract BackgroundLidocaineis a local anestheticthat wildly used in surgical treatment and postoperative medical care for lung cancers.We hypothesized thatlidocaine at clinical plasma concentrationcan inhibit CXCL12/CXCR4 axis regulated cytoskeletal remodeling thereby decrease migration ofNon-small-cell lung cancers (NSLC) cells. MethodsWe determined the effect of lidocaine at clinical plasma concentration on CXCL12-induced cell viability, apoptosis, cell death, monolayer cell wound healing rate, individual cell migration indicators, expression of CXCR4, CD44, and ICAM-1, intracellular Ca2+level, and filamentous actin level alteration of NSLC cells A549 and CXCR4-knocked down A549 cells using CCK-8, Bcl-2 ELISA, Cell death ELISA, wound healing assay, chemotaxis assay, western blotting, QPCR, Fura-2-based intracellular Ca2+assay, and Fluorescein Phalloidin staining respectively.ResultsLidocaine did not affect cell viability, apoptosis, and cell death but inhibited CXCL12-induced migration,intracellular Ca2+ releasing, and filamentous actin increase. Lidocaine decreased expression of CXCR4, increased CD44, but had no effect on ICAM-1. CXCL12induced the increase of CD44 and ICAM-1 but did not affect CD44 in the presence of lidocaine.The knockdown of CXCR4 eliminated all the effects of lidocaine.ConclusionLidocaine at clinical plasma concentrations inhibited CXCL12-induced CXCR4 activation, thereby reduced the intracellular Ca2+-dependent cytoskeleton remodeling, resulting in slower migration of A549 cells.

scholarly journals Calpeptin Induces Apoptosis in A549 Non-Small Cell Lung Cancer Cells

2021 ◽  
Author(s):  
Chiharu Tabata ◽  
Rie Tabata
Keyword(s):  
Lung Cancer ◽  
A549 Cells ◽  
Small Cell ◽  
Calpain Inhibitor ◽  
Small Cell Lung ◽  
Lung Cancers ◽  
Novel Treatments ◽  
Stage Disease ◽  
Induced Apoptosis ◽  
Nsclc Patients

Abstract Lung cancer is a leading cause of cancer-related death worldwide, and most are non-small cell lung cancers (NSCLC). Since the overall survival remains very poor for NSCLC patients with advanced-stage disease, the development of novel treatments is needed. Previous studies reported a relationship between calpain and tumorigenesis. In this study, we examined the apoptotic effects of calpeptin (Cal), a calpain inhibitor, on A549 NSCLC cells. We assessed whether Cal induced apoptosis in A549 cells. Cal induced apoptosis in A549 cells and also activated p38MAPK. These results suggest a possible clinical use of Cal for the treatment of NSCLC.

scholarly journals Anticancer activity of Asparagus racemosus root extracts in non-small cell lung cancer A549 cells

2018 ◽  
Vol 4 (6) ◽  
pp. 764-770 ◽  
Author(s):  
Debaashish Biswas ◽  
Manisha Mathur ◽  
Hemant Malhotra ◽  
Shipra Bhargava ◽  
Bharti Malhotra
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Anticancer Activity ◽  
Cell Lung Cancer ◽  
A549 Cells ◽  
Small Cell ◽  
Asparagus Racemosus ◽  
Small Cell Lung ◽  
Root Extracts

scholarly journals BMI1-Mediated Pemetrexed Resistance in Non-Small Cell Lung Cancer Cells Is Associated with Increased SP1 Activation and Cancer Stemness

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2069
Author(s):  
Huan-Ting Shen ◽  
Peng-Ju Chien ◽  
Shih-Hong Chen ◽  
Gwo-Tarng Sheu ◽  
Ming-Shiou Jan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Epithelial Mesenchymal Transition ◽  
A549 Cells ◽  
Small Cell ◽  
Small Cell Lung ◽  
Ki 67 ◽  
Lung Cancers ◽  
Mesenchymal Transition ◽  
Bmi1 Expression ◽  
Nsclc Patients

Lung cancer is the leading cause of cancer death worldwide and the therapeutic strategies include surgery, chemotherapy and radiation therapy. Non-small cell lung cancers (NSCLCs) account for around 85% of cases of lung cancers. Pemetrexed is an antifolate agent that is currently used as the second line chemotherapy drug in the treatment of advanced NSCLC patients with a response rate of 20–40%. The search for any combination therapy to improve the efficacy of pemetrexed is required. The existence of cancer stem cells (CSCs) is considered as the main reason for drug resistance of cancers. In this study, we first found that pemetrexed-resistant NSCLC cells derived from A549 cells displayed higher CSC activity in comparison to the parental cells. The expression of CSC related proteins, such as BMI1 or CD44, and the epithelial–mesenchymal transition (EMT) signature was elevated in pemetrexed-resistant NSCLC cells. We next discovered that the overexpression of BMI1 in A549 cells caused the pemetrexed resistance and inhibition of BMI1 by a small molecule inhibitor, PTC-209, or transducing of BMI1-specific shRNAs suppressed cell growth and the expression of thymidylate synthase (TS) in pemetrexed-resistant A549 cells. We further identified that BMI1 positively regulated SP1 expression and treatment of mithramycin A, a SP1 inhibitor, inhibited cell proliferation, as well as TS expression, of pemetrexed-resistant A549 cells. Furthermore, overexpression of BMI1 in A549 cells also caused the activation of EMT in and the enhancement of CSC activity. Finally, we demonstrated that pretreatment of PTC-209 in mice bearing pemetrexed-resistant A549 tumors sensitized them to pemetrexed treatment and the expression of Ki-67, BMI1, and SP1 expression in tumor tissues was observed to be reduced. In conclusion, BMI1 expression level mediates pemetrexed sensitivity of NSCLC cells and the inhibition of BMI1 will be an effective strategy in NSCLC patients when pemetrexed resistance has developed.

The tyrosine kinase TEK is differentially expressed in non-small cell lung adenocarcinomas.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
United States ◽  
Tyrosine Kinase ◽  
Lung Adenocarcinoma ◽  
Microarray Data ◽  
The United States ◽  
Small Cell ◽  
Small Cell Lung ◽  
Significant Differential Expression ◽  
Lung Cancers ◽  
Lung Adenocarcinomas

Non-small cell lung adenocarcinoma (NSCLC) is a leading cause of death in the United States and worldwide (1, 2). We mined published microarray data (3, 4, 5) to discover genes associated with NSCLC. We identified significant differential expression of the tyrosine kinase TEK in tumors from patients with NSCLC. TEK may be of relevance to the initiation, progression or maintenance of non-small cell lung cancers.

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