Concomitance of P-gp/LRP Expression with EGFR Mutations in Exons 19 and 21 in Non-Small Cell Lung Cancers

Hong, Wei; Lu, Weipeng; Li, Mei; Zhang, Qiuping; Shen, Lu

doi:10.3349/ymj.2016.57.1.50

Cited by 11 publications

(5 citation statements)

References 35 publications

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“…The mechanism of drug resistance in lung cancer is very complex, and many factors are involved. First, studies identified mechanisms associated with membrane-transport protein-mediated drug efflux pumps and associated with upregulation of membrane proteins with efflux functions, such as P-glycoprotein, MRP and LRP (38,40). Second, abnormal activation of intracellular enzyme systems, such as topoisomerase (Topo) and glutamyl transpeptidase, can combine with various chemotherapeutic drug, such as platinum compounds, melphalan, cyclophosphamide, chlorambucil, doxorubicin and nitrogen mustards to reduce their activity (41).…”

Section: Discussionmentioning

confidence: 99%

The CK2 inhibitor CX4945 reverses cisplatin resistance in the A549/DDP human lung adenocarcinoma cell line

2019

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Lung cancer negatively impacts global health, and the incidence of non-small cell lung cancer (NSCLC) is highest among all forms of lung cancer. Chemotherapy failure mainly occurs due to drug resistance; however, the associated molecular mechanism remains unclear. Casein kinase II (CK2), which plays important roles in the occurrence, development and metastasis of many tumours, regulates Wnt signaling by modulating β-catenin expression. In the present study the effects of the CK2 inhibitor, CX4945 on cisplatin [or cis-diamminedichloroplatinum (II); (DDP)]-resistant A549 cells (A549/DDP) were investigated to elucidate the underlying molecular mechanism. A549/DDP cells were divided into four groups (blank control, CX4945, cisplatin and CX4945+cisplatin). Cisplatin resistance was 5.16-fold greater in A549/DDP cells compared with that in A549 cells, with an optimal cisplatin concentration of 5 µg/ml. Moreover, levels of CK2, dishevelled-2 (DVL-2) phosphorylated (p) at Ser143 (p-DVL-2 Ser143), and major Wnt-signaling proteins were significantly higher in A549/DDP cells compared with that in A549 cells (P<0.05), with these levels further increased following cisplatin treatment (P<0.05), whereas these levels significantly decreased in A549 cells after cisplatin treatment (P<0.05). Additionally, multidrug-resistance-associated protein 1 and lung resistance protein expression was significantly higher in A549/DDP cells compared with that in A549 cells (P<0.05), with these levels increasing further in A549/DDP (P<0.05) but not A549 cells upon cisplatin treatment (P>0.05). In addition, reduced expression of resistance proteins in A549/DDP cells was accompanied by a decline in the 50% growth inhibition after CX4945 pre-treatment. Furthermore, levels of p-DVL-2 Ser143 and major Wnt-signaling proteins decreased significantly after treatment of A549/DDP cells with CX4945+cisplatin, whereas DVL-2 and p-DVL-2 Thr224 levels remained unchanged. Additionally, significant elevations in apoptosis rates in the CX4945+cisplatin group relative to the control and cisplatin-only groups, was observed (P<0.001). These results suggested that inhibiting Wnt/β-catenin signaling with CX4945, which attenuates levels of drug-resistanceassociated proteins and induces apoptosis, might reverse cisplatin resistance in NSCLC.

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Section: Discussionmentioning

confidence: 99%

The CK2 inhibitor CX4945 reverses cisplatin resistance in the A549/DDP human lung adenocarcinoma cell line

2019

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“…ARS-1620, another newly developed mutant-specific inhibitor of KRAS-G12C, has a strong inhibitory effect on KRAS-G12C mutant tumors ( Molina-Arcas et al, 2019 ). At the same time, the overexpression of the ABC transporter is one of the causes of MDR in tumor cells leading to chemotherapy failure, and while the relationship between ABC expression level and KRAS mutation in cancer cells can be confirmed ( Mohelnikova-Duchonova et al, 2013 ; Wei et al, 2016 ), the relationship between the expression level of ABC transporters and KRAS inhibitor is not clear, and the effect of ARS-1620 on ABCB1-mediated MDR has not been studied yet. Therefore, we investigated the potential interaction of ABCB1 with ARS-1620.…”

Section: Discussionmentioning

confidence: 99%

“…There has been considerable research regarding the relationship of expression levels of ABC transporters with KRAS mutations in cancer cells ( Mohelnikova-Duchonova et al, 2013 ; Wei et al, 2016 ), while the link between the level of ABC transporters and KRAS inhibitors is poorly understood. In this study, we investigated the connection between novel emerged KRAS-G12C inhibitor, ARS-1620, and ABCB1-overexpressing cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of ABCB1 Associated With the Resistance to the KRAS-G12C Specific Inhibitor ARS-1620 in Cancer Cells

et al. 2022

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The KRAS-G12C inhibitor ARS-1620, is a novel specific covalent inhibitor of KRAS-G12C, possessing a strong targeting inhibitory effect on KRAS-G12C mutant tumors. Overexpression of ATP-binding cassette super-family B member 1 (ABCB1/P-gp) is one of the pivotal factors contributing to multidrug resistance (MDR), and its association with KRAS mutations has been extensively studied. However, the investigations about the connection between the inhibitors of mutant KRAS and the level of ABC transporters are still missing. In this study, we investigated the potential drug resistance mechanism of ARS-1620 associated with ABCB1. The desensitization effect of ARS-1620 was remarkably intensified in both drug-induced ABCB1-overexpressing cancer cells and ABCB1-transfected cells as confirmed by cell viability assay results. This desensitization of ARS-1620 could be completely reversed when co-treated with an ABCB1 reversal agent. In mechanism-based studies, [3H] -paclitaxel accumulation assay revealed that ARS-1620 could be competitively pumped out by ABCB1. Additionally, it was found that ARS-1620 remarkably stimulated ATPase activity of ABCB1, and the HPLC drug accumulation assay displayed that ARS-1620 was actively transported out of ABCB1-overexpressing cancer cells. ARS-1620 acquired a high docking score in computer molecular docking analysis, implying ARS-1620 could intensely interact with ABCB1 transporters. Taken all together, these data indicated that ARS-1620 is a substrate for ABCB1, and the potential influence of ARS-1620-related cancer therapy on ABCB1-overexpressing cancer cells should be considered in future clinical applications.

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“…MDR1/P-gp expression is mainly mediated by alkylating agents (21). LRP serves an important role in various tumors, including gastric cancer and non-small cell lung cancer, with drug resistance (22,23). Its increased expression can mainly make tumor cells resistant to cisplatin (24).…”

Section: Discussionmentioning

confidence: 99%

Multidrug resistance affects the prognosis of primary epithelial ovarian cancer

et al. 2019

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Multidrug-resistant tumor cells can tolerate different structures, functions and antidrug action mechanisms, therefore, allowing these cells to respond to various structurally unrelated mechanisms of different chemotherapy drugs and to exhibit cross-resistance. The present study aimed to investigate the role of Multi-drug resistance gene (MDR1), Placental glutathione S-transferase-P1 (GSTP1), Lung resistance protein (LRP) and Ras association domain family member 1 (RASSF1A) in primary epithelial ovarian cancer (PEOC). The mRNA (protein) expression levels of MDR1, product P glycoprotein, LRP and GSTP1 were evaluated with reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis in all tissue samples, ovarian cancer cell line A2780 and A2780/DDP. Methylation-specific PCR (MSP) was used to detect RASSF1A gene methylation in all tissue samples. The resistance genes/proteins were either poorly or not expressed in A2780, however were highly expressed in A2780/DDP cell line. The expression of resistance genes/proteins decreased following different concentrations of zebularine-stimulated A2780/DDP. Hypermethylation and low expression of RASSF1A gene were detected in PEOC and A2780/DDP. Subsequent to being exposed to different concentrations of zebularine-stimulated A2780/DDP, the RASSF1A methylation level was decreased, while the unmethylation level was increased. The expression of RASSF1A gene/protein was gradually restored, and the gene/protein expression was enhanced with the increase in drug concentration. Multivariate logistic regression indicated that the expression level of gene LRP and GSTP1 was a risk factor for PEOC prognosis. Furthermore, the expression of LRP and GSTP1 in the negative-group survival curves was higher compared with the positive group. High expression of resistance genes may serve an important role in cancer primary resistance. Low expression caused by hyper-methylation of RASSF1A gene may serve an important role in cancer-acquired resistance in PEOC. The present study suggested that resistant gene expression may be a potential prognostic biomarker.

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Concomitance of P-gp/LRP Expression with EGFR Mutations in Exons 19 and 21 in Non-Small Cell Lung Cancers

Cited by 11 publications

References 35 publications

The CK2 inhibitor CX4945 reverses cisplatin resistance in the A549/DDP human lung adenocarcinoma cell line

The CK2 inhibitor CX4945 reverses cisplatin resistance in the A549/DDP human lung adenocarcinoma cell line

Overexpression of ABCB1 Associated With the Resistance to the KRAS-G12C Specific Inhibitor ARS-1620 in Cancer Cells

Multidrug resistance affects the prognosis of primary epithelial ovarian cancer

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