scholarly journals All-trans retinoic acid reduces cancer stem cell-like cell-mediated resistance to gefitinib in NSCLC adenocarcinoma cells

2020 ◽  
Author(s):  
Wenxiu Yao ◽  
Liyang Wang ◽  
Huan Huang ◽  
Xin Li ◽  
Pinjia Wang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Retinoic Acid ◽  
Cancer Stem Cell ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Ic50 Values

Abstract Background: The enrichment of cancer stem cell-like cells (CSCs) has been considered to be responsible for tumor progression after an initial response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small cell lung adenocarcinoma (NSCLC/ADC). CSCs with ALDH1A1 bright /CD44 high expression contribute to the TKIs resistance in NSCLC/ADC cells. All-trans retinoic acid (ATRA) has been shown to be a potential targeted therapy against CSCs due to its ability to inhibit ALDH1A1 activity. We therefore investigated whether ATRA could circumvent the resistance to improve the response to gefitinib in NSCLC/ADC cells. Methods: Treatment of NSCLC/ADC A549 and H1650 cells with gefitinib enriched the gefitinib surviving cells (GSCs). The expression of ALDH1A1 and CD44 and the IC50 values for gefitinib were determined by flow cytometry ( FCM ) and crystal violet assay in GSCs and ATRA-treated GSCs, respectively. Using DEAB as the positive control, direct inhibitory effect of ATRA on ALDH1A1 activity was determined by ALDEFLUOR assay, Results: GSCs showed higher expression of ALDH1A1 and CD44 and IC50 values for gefitinib than their respective parental cells , suggesting that gefitinib can lead to propagation of CSC -enriched gefitinib -resistant cells. Treatment with ATRA was found to significantly reduce the increased expression of ALDH1A1 and CD44 and the IC50 values for gefitinib in A549GSC and H1650GSC cells, and ATRA could directly inhibit active ALDH1A1 as compared to DEAB. Conclusion: Our findings suggest that combination treatment with ATRA prevents gefitinib-induced enrichment of ALDH1A1 bright /CD44 high CSCs and enhances gefitinib-induced growth inhibition of NSCLC/ADC cells. Key words : All-trans retinoic acid, ALDH1A1, CD44, EGFR tyrosine kinase inhibitors, non-small cell lung adenocarcinoma

scholarly journals All-trans retinoic acid reduces cancer stem cell-like cell-mediated resistance to gefitinib in NSCLC adenocarcinoma cells

2019 ◽  
Author(s):  
Wenxiu Yao ◽  
Liyang Wang ◽  
Huan Huang ◽  
Xin Li ◽  
Pinjia Wang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Retinoic Acid ◽  
Cancer Stem Cell ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Ic50 Values

Abstract Background: The enrichment of cancer stem cell-like cells (CSCs) has been considered to be responsible for tumor progression after an initial response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small cell lung adenocarcinoma (NSCLC/ADC). All-trans retinoic acid (ATRA) has been shown to potentiate cancer chemotherapy due to its ability to induce signals for CSC differentiation. We therefore investigated whether ATRA could improve the response of NSCLC/ADC cells to TKI gefitinib. Methods: Treatment of NSCLC/ADC A549 and H1650 cells with gefitinib enriched the gefitinib surviving cells (GSCs). The expression of ALDH1A1 and CD44 and the IC50 values for gefitinib were determined by flow cytometry (FCM) and crystal violet assay in GSCs and ATRA-treated GSCs, respectively. Results: GSCs showed higher expression of ALDH1A1 and CD44 and IC50 values for gefitinib than their respective parental cells, suggesting that gefitinib can lead to propagation of CSC-enriched gefitinib-resistant cells. Treatment with ATRA was found to significantly reduce the increased expression of ALDH1A1 and CD44 and the IC50 values for gefitinib in A549GSC and H1650GSC cells. Conclusion: Our findings suggest that combination treatment with ATRA prevents gefitinib-induced enrichment of ALDH1A1bright/CD44high CSCs and enhances gefitinib-induced growth inhibition of NSCLC/ADC cells. Key words: All-trans retinoic acid, ALDH1A1, CD44, EGFR tyrosine kinase inhibitors, non-small cell lung adenocarcinoma

scholarly journals All-trans retinoic acid reduces cancer stem cell-like cell-mediated resistance to gefitinib in NSCLC adenocarcinoma cells

2020 ◽  
Author(s):  
Wenxiu Yao ◽  
Liyang Wang ◽  
Huan Huang ◽  
Xin Li ◽  
Pinjia Wang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Retinoic Acid ◽  
Cancer Stem Cell ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Ic50 Values

Abstract Background: The enrichment of cancer stem cell-like cells (CSCs) has been considered to be responsible for tumor progression after an initial response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small cell lung adenocarcinoma (NSCLC/ADC). CSCs with ALDH1A1 bright /CD44 high expression contribute to the TKIs resistance in NSCLC/ADC cells. All-trans retinoic acid (ATRA) has been shown to be a potential targeted therapy against CSCs due to its ability to inhibit ALDH1A1 activity. We therefore investigated whether ATRA could circumvent the resistance to improve the response to gefitinib in NSCLC/ADC cells. Methods: Treatment of NSCLC/ADC A549 and H1650 cells with gefitinib enriched the gefitinib surviving cells (GSCs). The expression of ALDH1A1 and CD44 and the IC50 values for gefitinib were determined by flow cytometry ( FCM ) and crystal violet assay in GSCs and ATRA-treated GSCs, respectively. Using DEAB as the positive control, direct inhibitory effect of ATRA on ALDH1A1 activity was determined by ALDEFLUOR assay. Results: GSCs showed higher expression of ALDH1A1 and CD44 and IC50 values for gefitinib than their respective parental cells, suggesting that gefitinib can lead to propagation of CSC-enriched gefitinib-resistant cells. Treatment with ATRA was found to significantly reduce the increased expression of ALDH1A1 and CD44 and the IC50 values for gefitinib in A549GSC and H1650GSC cells, and ATRA could directly inhibit active ALDH1A1 as compared to DEAB. Conclusion: Our findings suggest that combination treatment with ATRA prevents gefitinib-induced enrichment of ALDH1A1 bright /CD44 high CSCs and enhances gefitinib-induced growth inhibition of NSCLC/ADC cells. Key words : All-trans retinoic acid, ALDH1A1, CD44, EGFR tyrosine kinase inhibitors, non-small cell lung adenocarcinoma

scholarly journals All-trans retinoic acid reduces cancer stem cell-like cell-mediated resistance to gefitinib in NSCLC adenocarcinoma cells

2020 ◽  
Author(s):  
Wenxiu Yao ◽  
Liyang Wang ◽  
Huan Huang ◽  
Xin Li ◽  
Pinjia Wang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Retinoic Acid ◽  
Cancer Stem Cell ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Initial Response ◽  
Inhibitory Effect ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Ic50 Values

Abstract Background: The enrichment of cancer stem cell-like cells (CSCs) has been considered to be responsible for tumor progression after an initial response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small cell lung adenocarcinoma (NSCLC/ADC). CSCs with ALDH1A1bright /CD44high expression contribute to the TKIs resistance in NSCLC/ADC cells. All-trans retinoic acid (ATRA) has been shown to be a potential targeted therapy against CSCs due to its ability to inhibit ALDH1A1 activity. We therefore investigated whether ATRA could circumvent the resistance to improve the response to gefitinib in NSCLC/ADC cells.Methods: Treatment of NSCLC/ADC A549 and H1650 cells with gefitinib enriched the gefitinib surviving cells (GSCs). The expression of ALDH1A1 and CD44 and the IC50 values for gefitinib were determined by flow cytometry (FCM) and crystal violet assay in GSCs and ATRA-treated GSCs, respectively. Using DEAB as the positive control, direct inhibitory effect of ATRA on ALDH1A1 activity was determined by ALDEFLUOR assay, Results: GSCs showed higher expression of ALDH1A1 and CD44 and IC50 values for gefitinib than their respective parental cells, suggesting that gefitinib can lead to propagation of CSC-enriched gefitinib-resistant cells. Treatment with ATRA was found to significantly reduce the increased expression of ALDH1A1 and CD44 and the IC50 values for gefitinib in A549GSC and H1650GSC cells, and ATRA could directly inhibit active ALDH1A1 as compared to DEAB.Conclusion: Our findings suggest that combination treatment with ATRA prevents gefitinib-induced enrichment of ALDH1A1bright/CD44high CSCs and enhances gefitinib-induced growth inhibition of NSCLC/ADC cells.

Randomized Phase II Trial of All-Trans-Retinoic Acid With Chemotherapy Based on Paclitaxel and Cisplatin As First-Line Treatment in Patients With Advanced Non–Small-Cell Lung Cancer

2010 ◽  
Vol 28 (21) ◽  
pp. 3463-3471 ◽  
Author(s):  
Oscar Arrieta ◽  
Claudia H. González-De la Rosa ◽  
Elena Aréchaga-Ocampo ◽  
Geraldine Villanueva-Rodríguez ◽  
Tania L. Cerón-Lizárraga ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Retinoic Acid ◽  
Phase Ii Trial ◽  
Small Cell ◽  
Toxicity Profile ◽  
Small Cell Lung ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Randomized Phase Ii ◽  
To Receive

Purpose This randomized phase II trial evaluated whether the combination of cisplatin and paclitaxel (PC) plus all-trans retinoic acid (ATRA) increases response rate (RR) and progression-free survival (PFS) in patients with advanced non–small-cell lung cancer (NSCLC) with an acceptable toxicity profile and its association with the expression of retinoic acid receptor beta 2 (RAR-β2) as a response biomarker. Patients and Methods Patients with stages IIIB with pleural effusion and IV NSCLC were included to receive PC, and randomly assigned to receive ATRA 20 mg/m2/d (RA/PC) or placebo (P/PC) 1 week before treatment until two cycles were completed. RAR-β2 expression was analyzed in tumor and adjacent lung tissue. Results One hundred seven patients were included, 55 in the P/PC group and 52 in the RA/PC group. RR for RA/PC was 55.8% (95% CI, 46.6% to 64.9%) and for P/PC, 25.4% (95% CI, 21.3 to 29.5%; P = .001). The RA/PC group had a longer median PFS (8.9 v 6.0 months; P = .008). Multivariate analysis of PFS showed significant differences for the RA/PC group (hazard ratio, 0.62; 95% CI, 0.4 to 0.95). No significant differences in toxicity grade 3/4 were found between groups, except for hypertriglyceridemia (10% v 0%) in RA/PC (P = .05). Immunohistochemistry and reverse-transcriptase polymerase chain reaction assays showed expression of RAR-β2 in normal tissues of all tumor samples, but only 10% of samples in the tumor tissue. Conclusion Adding ATRA to chemotherapy could increase RR and PFS in patients with advanced NSCLC with an acceptable toxicity profile. A phase III clinical trial is warranted to confirm these findings.

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