scholarly journals Decitabine Sensitizes the Radioresistant Lung Adenocarcinoma to Pemetrexed Through Upregulation of Folate Receptor Alpha

2021 ◽  
Vol 11 ◽  
Author(s):  
Yuqing Wang ◽  
Jie Huang ◽  
Qiong Wu ◽  
Jingjing Zhang ◽  
Zhiyuan Ma ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Folate Receptor ◽  
Critical Role ◽  
Subsequent Treatment ◽  
Folate Receptor Alpha ◽  
Fractionated Radiotherapy ◽  
Receptor Alpha ◽  
Regulatory Approach ◽  
Promising Treatment

Chemotherapy is the backbone of subsequent treatment for patients with lung adenocarcinoma (LUAD) exhibiting radiation resistance, and pemetrexed plays a critical role in this chemotherapy. However, few studies have assessed changes in the sensitivity of LUAD cells to pemetrexed under radioresistant circumstances. Therefore, the objectives of this study were to delineate changes in the sensitivity of radioresistant LUAD cells to pemetrexed and to elucidate the related mechanisms and then develop an optimal strategy to improve the cytotoxicity of pemetrexed in radioresistant LUAD cells. Our study showed a much lower efficacy of pemetrexed in radioresistant cells than in parental cells, and the mechanism of action was the significant downregulation of folate receptor alpha (FRα) by long-term fractionated radiotherapy, which resulted in less cellular pemetrexed accumulation. Interestingly, decitabine effectively reversed the decrease in FRα expression in radioresistant cells through an indirect regulatory approach. Thereafter, we designed a combination therapy of pemetrexed and decitabine and showed that the activation of FRα by decitabine sensitizes radioresistant LUAD cells to pemetrexed both in vitro and in xenografts. Our findings raised a question regarding the administration of pemetrexed to patients with LUAD exhibiting acquired radioresistance and accordingly suggested that a combination of pemetrexed and decitabine would be a promising treatment strategy.

Antibody-independent ApoStream technology isolates folate receptor alpha (FRA)–positive circulating tumor cells from blood of non-small cell lung adenocarcinoma patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e21028-e21028
Author(s):  
Darren W. Davis ◽  
Christopher Neal ◽  
Vishal Gupta ◽  
Vladislava O. Melnikova ◽  
Jacky Woo ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Folate Receptor ◽  
Small Cell ◽  
Normal Donor ◽  
Small Cell Lung ◽  
Folate Receptor Alpha ◽  
Receptor Alpha ◽  
Nsclc Patients

e21028 Background: The ability to enrich and interrogate circulating tumor cells (CTCs) from blood may allow for the analysis of metastatic dissemination and potential use of CTCs as surrogates for monitoring drug efficacy. We developed ApoStream, a dieletrophoresis field-flow fractionation based platform, for antibody-independent CTC isolation. We demonstrated that ApoStream successfully isolates non-small cell lung adenocarcinoma (NSCLC) CTCs that express Folate Receptor alpha (FRA), a GPI-anchored receptor, which has emerged as a cancer biomarker and potential therapeutic target in multiple cancer types. Methods: ApoStream technology was used to enrich CTCs from NSCLC patients’ blood. CTC enrichment by ApoStream was compared to that of the FDA cleared CellSearch CTC kit. A multiplexed immunofluorescent assay was developed to enable CTC enumeration (Cytokeratin+/CD45-/DAPI+ cells) and analysis of FRA expression (detection by murine antibody clone 26B3) using single cell quantitative laser scanning cytometry (LSC). Results: In a side-by-side comparison with the CellSearch CTC kit, ApoStream isolated significantly higher numbers of CTCs in 9 metastatic adenocarcinoma NSCLC patients (Apostream: mean =139, range 3-487 per 7.5 mL of blood, versus CellSearch kit: mean =2, range 0-8 per 7.5 mL of blood, n= 9, p=0.041). All patients were found to be CTC-positive by ApoStream, while only 3 of 9 (33%) patients were CTC-positive based on the CellSearch kit. LSC analysis demonstrated that 8-33% of all CTCs isolated expressed FRA and that FRA expression was confined to CTCs only. No false positive CTCs and no FRA-expressing cells were isolated by ApoStream from normal donor blood (n=15). Conclusions: All NSCLC adenocarcinoma patients analyzed had FRA-positive CTCs, suggesting that FRA may play a key role in metastasis and that screening of patients with the ApoStream CTC isolation system may identify patients who could benefit from FRA-targeted therapy.

MORAb-003 inhibits folate-driven growth mediated by the human folate receptor alpha

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10108-10108
Author(s):  
E. Routhier ◽  
H. Turchin ◽  
R. Patel ◽  
W. Ebel ◽  
P. Sass ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cho Cells ◽  
Cellular Proliferation ◽  
Folate Receptor ◽  
Dependent Manner ◽  
Phase I Clinical Trials ◽  
Folate Receptor Alpha ◽  
Receptor Alpha ◽  
Human Folate Receptor

10108 Background: MORAb-003 is a therapeutic humanized antibody currently in Phase I clinical trials for advanced ovarian cancer, and is directed against the human folate receptor alpha (FRα), an antigen which is highly overexpressed on the surface of the majority of ovarian cancers. Overexpression of FRα has been shown to confer a growth advantage to tumorigenic cells in vitro, under conditions of reduced folate availability. We have previously determined that MORAb-003 elicits robust antibody-dependent cellular cytotoxicity (ADCC) and complement-directed cytotoxicity (CDC) in vitro, and is effective in mouse xenograft models of human ovarian cancer. We now show that MORAb-003 possesses novel, growth-inhibitory functions distinct from its immune effector properties. This activity can be recapitulated, using a cell-based assay to score inhibition of folate-dependent growth. Methods: Chinese Hamster Ovary (CHO) cells were engineered to express surface FRα. The cells were cultured under a low folate (< 20 nM) regimen, then re-fed medium supplemented with various concentrations (0–10 μM) of 5-methyltetrahydrofolate (5-MTF), a folate preferentially internalized by the FRα. Cellular proliferation was measured as a function of added 5-MTF, in the presence or absence of MORAb-003. Results: FRα-expressing CHO cells were found to require approximately 100-fold lower 5-MTF than a matched, non-expressing cell line. This increased proliferation could be reduced in a concentration-dependent manner by MORAb-003. Conclusions: MORAb-003 can antagonize the activity of human FRα, resulting in the loss of growth advantage conferred by overexpression of FRα under conditions which bracket physiological (10–100 nM) folate concentrations. [Table: see text]

scholarly journals Long Non-coding RNA ST8SIA6-AS1 Promotes Lung Adenocarcinoma Progression Through Sponging miR-125a-3p

2020 ◽  
Vol 11 ◽  
Author(s):  
Qifeng Cao ◽  
Weiqin Yang ◽  
Xili Ji ◽  
Wei Wang
Keyword(s):  
Lung Adenocarcinoma ◽  
Critical Role ◽  
Diagnosis And Prognosis ◽  
Non Coding Rna ◽  
Cancer Types ◽  
Promising Treatment ◽  
Plasma Depletion ◽  
Long Non Coding Rna

Emerging evidence suggests that long non-coding RNA (lncRNA) plays a critical role in human disease progression. Recently, a novel lncRNA ST8SIA6-AS1 was shown as an important driver in various cancer types. Nevertheless, its contribution to lung adenocarcinoma (LUAD) remains undocumented. Herein, we found that ST8SIA6-AS1 was frequently overexpressed in LUAD cell lines, tissues, and plasma. Depletion of ST8SIA6-AS1 significantly inhibited LUAD cell proliferation and invasion in vitro and tumor growth in vivo. In term of mechanism, ST8SIA6-AS1 was transcriptionally repressed by tumor suppressor p53, and ST8SIA6-AS1 was mainly located in the cytoplasm and could abundantly sponge miR-125a-3p to increase nicotinamide N-methyltransferase (NNMT) expression, thereby facilitating LUAD malignant progression. Clinically, high ST8SIA6-AS1 was positively correlated with larger tumor size, lymph node metastasis, and later TNM stage. Moreover, ST8SIA6-AS1 was identified as an excellent indicator for MM diagnosis and prognosis. Collectively, our data demonstrate that ST8SIA6-AS1 is a carcinogenic lncRNA in LUAD, and targeting the axis of ST8SIA6-AS1/miR-125a-3p/NNMT may be a promising treatment for LUAD patients.

scholarly journals Correlation between folate receptor alpha (FRα) expression and clinicopathological features in lung adenocarcinoma

2019 ◽  
Vol 30 ◽  
pp. ii2
Author(s):  
N. Tamura ◽  
Y. Fujiwara ◽  
T. Hashimoto ◽  
H. Shiraishi ◽  
S. Kitano ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Folate Receptor ◽  
Clinicopathological Features ◽  
Folate Receptor Alpha ◽  
Receptor Alpha

scholarly journals Investigating the Potential of Conjugated Selenium Redox Folic Acid as a Treatment for Triple Negative Breast Cancer

Antioxidants ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 138 ◽  
Author(s):  
Soni Khandelwal ◽  
Mallory Boylan ◽  
Gilbert Kirsch ◽  
Julian E. Spallholz ◽  
Lauren S. Gollahon
Keyword(s):  
Breast Cancer ◽  
Folic Acid ◽  
Cell Line ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Folate Receptor ◽  
Folate Receptor Alpha ◽  
Receptor Alpha ◽  
Redox Active

Previous studies have demonstrated that redox selenium compounds arrest cancer cell viability in vitro through their pro-oxidative activity by generating superoxide (O2•−). Currently, there are no efficacious treatment options for women with Triple Negative Breast Cancer (TNBC). However, the association between the over-expression of the Folate Receptor Alpha (FRA) in TNBC and other cancer cells, has led to the possibility that TNBCs might be treated by targeting the FRA with redox selenium covalent Folic Acid conjugates. The present study reports the synthesis of the redox active vitamer, Selenofolate, generating superoxide. Superoxide (O2•−) catalytic generation by Selenofolate was assessed by an in vitro chemiluminescence (CL) assay and by a Dihydroethidium (DHE) in vivo assay. Cytotoxicity of Selenofolate was assessed against the TNBC cell line MDA-MB-468 and an immortalized, mammary epithelial cell line, HME50-5E. Cytotoxicity of Selenofolate was compared to Folic Acid and sodium selenite, in a time and dose dependent manner. Selenofolate and selenite treatments resulted in greater inhibition of MDA-MB-468 cell proliferation than HME50-5E as evaluated by Trypan Blue exclusion, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) metabolic assay and Annexin V apoptosis assays. Folate receptor alpha (FRA) protein expression was assessed by Western blotting, with the experimental results showing that redox active Selenofolate and selenite, but not Folic Acid, was cytotoxic to MDA-MB-468 cells in vitro, suggesting a possible clinical option for treating TNBC and other cancers over-expressing FRA.

Correlation between the expression of folate receptor alpha (FRα) and clinicopathological features in patients with lung adenocarcinoma

Lung Cancer ◽  
2020 ◽  
Vol 145 ◽  
pp. 152-157 ◽  
Author(s):  
Nobumasa Tamura ◽  
Yutaka Fujiwara ◽  
Taiki Hashimoto ◽  
Hideaki Shiraishi ◽  
Shigehisa Kitano ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Folate Receptor ◽  
Clinicopathological Features ◽  
Folate Receptor Alpha ◽  
Receptor Alpha
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