Silencing circPVT1 enhances radiosensitivity in non-small cell lung cancer by sponging microRNA-1208

2021 ◽  
pp. 1-17
Author(s):  
Meifang Huang ◽  
Tianqian Li ◽  
Qing Wang ◽  
Chongxin Li ◽  
Huahua Zhou ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Underlying Mechanism ◽  
Small Cell ◽  
Nsclc Cell ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Luciferase Reporter ◽  
Small Cell Lung ◽  
Irradiation Treatment

BACKGROUND: Radiotherapy is one of main useful therapies in non-small cell lung cancer (NSCLC). Nevertheless, the underlying mechanism between NSCLC cell radiosensitivity and effective treatment remains unclear. OBJECTIVE: The aim is to explore the relationship between circular (circ) RNA and NSCLC cell radiosensitivity. METHODS: CircRNA plasmacytoma variant translocation 1 (PVT1) and microRNA (miR)-1208 expression in NSCLC cells were assessed using quantitative reverse transcriptase PCR (qRT-PCR). NSCLC cells were transfected with si-PVT1 or miR-1208 inhibitor and then exposed to irradiation. Cellular biology behaviors were detected using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL), colony formation, invasion and western blot. Additionally, binding between circPVT1 and miR-1208 was testified by dual-luciferase reporter and RIP assay. RESULTS: CircPVT1 was upregulated in NSCLC cells after irradiation treatment. Silencing circPVT1 induced inhibition of NSCLC cell growth and invasion, accompanied by cell apoptosis and γ-H2AX expression. Moreover, NSCLC cell proliferation and invasion was further inhibited by irradiation treatment in circPVT1-silenced cells, indicating a strong radiosensitivity of NSCLC cells. CircPVT1 functions as a competing endogenous RNA towards miR-1208. Silencing miR-1208 reversed NSCLC cell sensitivity response to irradiation and activated PI3K/AKT/mTOR pathway in circPVT1-silenced cells. CONCLUSIONS: Silencing circPVT1 enhanced radiosensitivity of NSCLC cells by sponging miR-1208.

scholarly journals MiR-7-5p suppresses tumor metastasis of non-small cell lung cancer by targeting NOVA2

2019 ◽  
Vol 24 (1) ◽  
Author(s):  
Haiping Xiao
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Tumor Metastasis ◽  
Underlying Mechanism ◽  
Small Cell ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Small Cell Lung

Abstract Background Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. Distant metastasis is thought to be one of the most important factors responsible for the failure of NSCLC therapy. MicroRNA-7-5p (miR-7-5p) has been demonstrated to be a tumor suppressor in breast cancer, hepatocarcinoma, prostate cancer and glioblastoma multiforme (GBM). However, its role in NSCLC is still not fully understood. This study evaluated the role of miR-7-5p in the progression of NSCLC and explored the underlying mechanism. Materials & methods The quantitative real-time PCR (qPCR), MTT, migration and invasion assays were used to evaluate the effects of miR-7-5p on the proliferation, migration and invasion of A549 and SPCA-1 cells. A tumor xenograft model was created to determine the effects of miR-7-5p on metastasis in vivo. The dual-luciferase reporter gene, neuro-oncological ventral antigen 2 (NOVA2) overexpression and western blotting assays were performed to explore the underlying mechanism. Results MiR-7-5p is downregulated in NSCLC tissues and lung cancer cell lines. It suppresses proliferation, migration, invasion and EMT marker expression in vitro and in vivo. Further study showed that miR-7-5p suppresses tumor metastasis of NSCLC by targeting NOVA2. Overexpression of NOVA2 attenuates the miR-7-5p-mediated inhibitory effect on lung cancer cells. Conclusion MiR-7-5p suppresses NSCLC metastasis. Targeting miR-7-5p may contribute to the success of NSCLC therapy.

scholarly journals Long noncoding RNA HOXA-AS2 promotes non-small cell lung cancer progression by regulating miR-520a-3p

2019 ◽  
Vol 39 (5) ◽  
Author(s):  
Yunpeng Liu ◽  
Xingyu Lin ◽  
Shiyao Zhou ◽  
Peng Zhang ◽  
Guoguang Shao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Nsclc Cell ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Small Cell Lung

Abstract Background: The HOXA cluster antisense RNA 2 (HOXA-AS2) has recently been discovered to be involved in carcinogenesis in multiple cancers. However, the role and underlying mechanism of HOXA-AS2 in non-small cell lung cancer (NSCLC) yet need to be unraveled. Methods: HOXA-AS2 expression in NSCLC tissues and cell lines was detected using quantitative real-time PCR (qRT-PCR). Furthermore, the effects of HOXA-AS2 on NSCLC cell proliferation, apoptosis, migration, and invasion were assessed by MTS, flow cytometry, wound healing and transwell invasion assays, respectively. Starbase2.0 predicted and luciferase reporter and RNA immunoprecipitation (RIP) assays were used to validate the association of HOXA-AS2 and miR-520a-3p in NSCLC cells. Results: Our results revealed that HOXA-AS2 in NSCLC tissues were up-regulated and cell lines, and were associated with poor prognosis and overall survival. Further functional assays demonstrated that HOXA-AS2 knockdown significantly inhibited NSCLC cell proliferation, induced cell apoptosis and suppressed migration and invasion. Starbase2.0 predicted that HOXA-AS2 sponge miR-520a-3p at 3′-UTR, which was confirmed using luciferase reporter and RIP assays. miR-520a-3p expression was inversely correlated with HOXA-AS2 expression in NSCLC tissues. In addition, miR-520a-3p inhibitor attenuated the inhibitory effect of HOXD-AS2-depletion on cell proliferation, migration and invasion of NSCLC cells. Moreover, HOXA-AS2 could regulate HOXD8 and MAP3K2 expression, two known targets of miR-520a-3p in NSCLC. Conclusion: These findings implied that HOXA-AS2 promoted NSCLC progression by regulating miR-520a-3p, suggesting that HOXA-AS2 could serve as a therapeutic target for NSCLC.

scholarly journals Exosomal miR-3180-3p Inhibits Proliferation and Metastasis of Non-Small Cell Lung Cancer by Downregulating FOXP4

2020 ◽  
Author(s):  
Tengfei Chen ◽  
Yali Liu ◽  
Chang Li ◽  
Chun Xu ◽  
Cheng Ding ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Nsclc Cell ◽  
Luciferase Reporter ◽  
Small Cell Lung ◽  
Gene Assay ◽  
Proliferation And Metastasis

Abstract Background: Non-small cell lung cancer (NSCLC) is the most malignant cancers worldwide, but the pathogenesis is not completely known. In this study, we explored the function and mechanism of exosomes transferring miR-3180-3p in NSCLC progression.Method: The expression of miR-3180-3p of NSCLC tissues and para-carcinoma tissues was from the GEO database (GEO: GSE53882). The exosomes derived from A549 cells were identified. The proliferation, migration and invasion were measured after treatment with exosomal miR-3180-3p or transfected by miR-3180-3p mimics. The relationship between miR-3180-3p and forkhead box P4 (FOXP4) was predicted by bioinformatics tool and measured dual-luciferase reporter gene assay and western blotting. At last, mouse xenograft model of NSCLC cells was established to verify the function of exosomal miR-3180-3p in vivo.Results: We found that miR-3180-3p decreased in both NSCLC cell lines and patient tissues. Overexpression of miR-3180-3p or treatment with exosomal miR-3180-3p significantly repressed the cell proliferation and metastasis in NSCLC cell lines. Subsequently, we found miR-3180-3p performed function by downregulating FOXP4 protein expression. Furthermore, the volume and weight of nude mice tumor which expressed exosomal miR-3180-3p was significantly reduced. Conclusion: Exosomal miR-3180-3p suppresses NSCLC progression by downregulating FOXP4 expression.

scholarly journals Long Non-coding RNA LINC00847 Induced by E2F1 Accelerates Non-small Cell Lung Cancer Progression Through Targeting miR-147a/IFITM1 Axis

2021 ◽  
Vol 8 ◽  
Author(s):  
Huan Li ◽  
Yao-kai Chen ◽  
Qiu Wan ◽  
An-qi Shi ◽  
Min Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Cell Lung Cancer ◽  
Molecular Mechanisms ◽  
Small Cell ◽  
Nsclc Cell ◽  
Luciferase Reporter ◽  
Well Test ◽  
Small Cell Lung

Background: Long non-coding RNAs (lncRNAs) can remarkably regulate human malignancies in terms of the development and the progression. Previously, lncRNA LINC00847 (LINC00847) has been reported to present dysregulation in several tumors. However, the expression and function of LINC00847 in non-small cell lung cancer (NSCLC) have not been investigated.Methods: RT-qPCR was performed to determine the expressions of LINC00847 in collected tissue samples and cell lines. The clinical significance of LINC00847 was statistically analyzed. CCK-8 test, cell scratch test and trans-well test were used to evaluate the proliferation, invasion and migration abilities of NSCLC cells, respectively. The xenograft tumor model was constructed to confirm the effects of LINC00847 knockdown on NSCLC in vivo. Further, luciferase reporter assays and Western blot were performed to explore molecular mechanisms underlying the functions of LINC00847.Results: Increased expressions of LINC00847 were observed in NSCLC samples as well as cell lines. Additionally, E2F1 could be capable of directly binding to the LINC00847 promoter region, followed by promoting its expression. Clinically, LINC00847 high-expression could lead to poor prognosis of NSCLC patients. Functionally, LINC00847 knockdown noticeably repressed NSCLC cell growth and metastasis. Mechanically, miR-147a/IFITM1 axis was a downstream target of LINC00847, and silencing of miR-147a could rescue the anti-cancer effects of LINC00847 knockdown on NSCLC cell behaviors.Conclusion: Overall, up regulation of LINC00847 induced by E2F1 promoted the progression of NSCLC by modulating miR-147a/IFITM1 axis, representing a novel regulatory mechanism for NSCLC progression.

scholarly journals Exosome-Mediated miR-7-5p Delivery Enhances the Anticancer Effect of Everolimus via Blocking MNK/eIF4E Axis in Non-Small Cell Lung Cancer

2021 ◽  
Author(s):  
Sile Liu ◽  
Weiyuan Wang ◽  
Yue Ning ◽  
Hongmei Zheng ◽  
Yuting Zhan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Western Blot ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Therapeutic Efficacy ◽  
Mtor Inhibitors ◽  
Small Cell ◽  
Nsclc Cell ◽  
Luciferase Reporter ◽  
Small Cell Lung

Abstract Background Everolimus is a kind of mTOR inhibitors. Activated mitogen-activated protein kinase interacting kinases/eukaryotic translation initiation factor 4E (MNK/eIF4E) axis plays a crucial role in resistance to Everolimus in non-small cell lung cancer (NSCLC). Typically, eIF4E phosphorylation increased by mTOR inhibitors was mainly mediated by MNKs. But the mechanisms are poorly understood. Recently, extensive reprogramming of miRNA profiles has also been found after long-term mTOR inhibitor exposing. Our previous studies have confirmed that tumor suppressor miR-7-5p was decreased in A549 cells after treatment with Everolimus. Exactly, MNK1 is the target of miR-7-5p. Here, we investigated the biological functions and potential molecular mechanisms of miR-7-5p in the NSCLC undergoing treatment with Everolimus. Methods miR-7-5p level and expression of main markers of MNK/eIF4E axis were evaluated by qRT-PCR, western blot, in situ hybridization, and immunohistochemistry on NSCLC cell lines and human NSCLC samples. Proliferation, migration and invasion of NSCLC cells in culture were explored by Colony formation, CCK-8, Wound healing and Transwell assays. NSCLC cell tumorigenicity was assessed by xenotransplants in nude mice. Targeted binding of miR-7-5p to MNK1 was confirmed by the Dual-luciferase reporter assay. And the isolation and identification of exosomes were investigated by Invitrogen™ Total Exosome RNA Isolation Kit, western blot, transmission electron microscopy and Zetasizer Nano ZS90 instrument. Results Everolimus targeted mTORC1 inducing NSCLC cells to secrete miR-7-5p-loaded exosomes in Rab27A and Rab27B dependent manners. Loss of intracellular miR-7-5p induced phosphorylation of MNK/eIF4E axis, but supplement of extra exosomal miR-7-5p could reverse it. Of note, both lower expression of miR-7-5p and elevated MNK1 protein were associated with poor prognosis of NSCLC. Both endogenous miR-7-5p and exo-miR-7-5p enhanced the therapeutic efficacy of Everolimus through inhibiting the proliferation, migration, and metastasis of NSCLC in vitro and vivo. Combination of miR-7-5p with Everolimus induced apoptosis to exhibit a synergistic anticancer therapeutic efficacy via dual abrogation of MNK/eIF4E and mTOR in NSCLC. Conclusion Everolimus decreases the intracellular miR-7-5p levels through release of miR-7-5p loaded exosomes from NSCLC cells in Rab27A and Rab27B dependent manners. Either endogenous miR-7-5p or exo-miR-7-5p combined with Everolimus can enhance the anticancer efficacy via targeting MNK/eIF4E axis and mTOR. Therefore, exosome-mediated miR-7-5p delivery combined with Everolimus may be considered as a promising novel combined therapeutic strategy for NSCLC.

scholarly journals The Long Non-Coding RNA XIST Controls Non-Small Cell Lung Cancer Proliferation and Invasion by Modulating miR-186-5p

2017 ◽  
Vol 41 (6) ◽  
pp. 2221-2229 ◽  
Author(s):  
Haoyou Wang ◽  
Qiming Shen ◽  
Xin Zhang ◽  
Chunlu Yang ◽  
Su Cui ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Molecular Mechanisms ◽  
Small Cell ◽  
Nsclc Cell ◽  
Luciferase Reporter ◽  
Small Cell Lung ◽  
Proliferation And Invasion

Background/Aims: Long non-coding RNAs (lncRNAs) are key players in the development and progression of human cancers. The lncRNA XIST (X-inactive specific transcript) has been shown to be upregulated in human non-small cell lung cancer (NSCLC); however, its role and molecular mechanisms in NSCLC cell progression remain unclear. Methods: qRT-PCR was conducted to assess the expression of XIST and miR-186. Cell proliferation was detected using MTT assay. Cell invasion and migration were evaluated using transwell assay. Cell cycle distribution and apoptosis rates were analyzed by flow cytometry. Luciferase reporter assay was used to identify the direct regulation of XIST and miR-186. A RNA immunoprecipitation was used to analyze whether XIST was associated with the RNA-induced silencing complex (RISC). Results: We confirmed that XIST was upregulated in NSCLC cell lines and tissues. Functionally, XIST knockdown inhibited cancer cell proliferation and invasion, and induced apoptosis in vitro, and suppressed subcutaneous tumor growth in vivo. Mechanistic investigations revealed a reciprocal repressive interaction between XIST and miR-186-5p. Furthermore, we showed that miR-186-5p has a binding site for XIST. Our data also indicated that XIST and miR-186-5p are likely in the same RNA induced silencing complex. Conclusion: Together, our data revealed that XIST knockdown confers suppressive function in NSCLC and XIST may be a novel therapeutic marker in this disease.

The Key microRNAs Regulated the Development of Non-small Cell Lung Cancer by Targeting TGF-β-induced epithelial–mesenchymal Transition

2019 ◽  
Vol 22 (4) ◽  
pp. 238-244 ◽  
Author(s):  
Gang Chen ◽  
Bo Ye
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Nsclc Cell ◽  
Normal Lung ◽  
Migration And Invasion ◽  
Small Cell Lung ◽  
Mesenchymal Transition

Purpose: Epithelial-to-Mesenchymal Transition (EMT) was reported to play a key role in the development of Non-Small Cell Lung Cancer (NSCLC). The process of EMT is regulated by the changes of miRNAs expression. However, it is still unknown which miRNA changed the most in the process of canceration and whether these changes played a role in tumor development. Methods: A total of 36 SCLC patients treated in our hospital between 11th, 2015 and 10th, 2017 were enrolled. The samples of cancer tissues and paracancer tissues of patients were collected and analyzed. Then, the miRNAs in normal lung cells and NSCLC cells were also analyzed. In the presence of TGF-β, we transfected the miRNA mimics or inhibitor into NSCLC cells to investigate the role of the significantly altered miRNAs in cell migration and invasion and in the process of EMT. Results: MiR-330-3p was significantly up-regulated in NSCLC cell lines and tissues and miRNA- 205 was significantly down-regulated in NSCLC cell lines and NSCLC tissues. Transfected miRNA-205 mimics or miRMA-330-3p inhibitor inhibited the migration and invasion of NCIH1975 cell and restrained TGF-β-induced EMT in NSCLC cells. Conclusion: miRNA-330-3p and miRNA-205 changed the most in the process of canceration in NSCLC. Furthermore, miR-330-3p promoted cell invasion and metastasis in NSCLC probably by promoting EMT and miR-205 could restrain NSCLC likely by suppressing EMT.

scholarly journals Midazolam increases cisplatin-sensitivity in non-small cell lung cancer (NSCLC) via the miR-194-5p/HOOK3 axis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Tingting Sun ◽  
Jing Chen ◽  
Xuechao Sun ◽  
Guonian Wang
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Cell Apoptosis ◽  
Cisplatin Resistance ◽  
Small Cell ◽  
Luciferase Reporter ◽  
Small Cell Lung ◽  
Cisplatin Sensitivity

Abstract Backgrounds As previously reported, midazolam anesthesia exerts tumor-suppressing effects in non-small cell lung cancer (NSCLC), but the regulating effects of this drug on cisplatin-resistance in NSCLC have not been studied. Thus, we designed this study to investigate this issue and preliminarily delineate the potential molecular mechanisms. Methods We performed MTT assay and trypan blue staining assay to measure cell proliferation and viability. Cell apoptosis was examined by FCM. qRT-PCR and immunoblotting were performed to determine the expression levels of genes. The targeting sites between genes were predicted by bioinformatics analysis and were validated by dual-luciferase reporter gene system assay. Mice tumor-bearing models were established and the tumorigenesis was evaluated by measuring tumor weight and volume. Immunohistochemistry (IHC) was used to examine the pro-proliferative Ki67 protein expressions in mice tumor tissues. Results The cisplatin-resistant NSCLC (CR-NSCLC) cells were treated with high-dose cisplatin (50 μg/ml) and low-dose midazolam (10 μg/ml), and the results showed that midazolam suppressed cell proliferation and viability, and promoted cell apoptosis in cisplatin-treated CR-NSCLC cells. In addition, midazolam enhanced cisplatin-sensitivity in CR-NSCLC cell via modulating the miR-194-5p/hook microtubule-tethering protein 3 (HOOK3) axis. Specifically, midazolam upregulated miR-194-5p, but downregulated HOOK3 in the CR-NSCLC cells, and further results validated that miR-194-5p bound to the 3’ untranslated region (3’UTR) of HOOK3 mRNA for its inhibition. Also, midazolam downregulated HOOK3 in CR-NSCLC cells by upregulating miR-194-5p. Functional experiments validated that both miR-194-5p downregulation and HOOK3 upregulation abrogated the promoting effects of midazolam on cisplatin-sensitivity in CR-NSCLC cells. Conclusions Taken together, this study found that midazolam anesthesia reduced cisplatin-resistance in CR-NSCLC cells by regulating the miR-194-5p/HOOK3 axis, implying that midazolam could be used as adjuvant drug for NSCLC treatment in clinical practices.

scholarly journals Tin Mesoporphyrin Selectively Reduces Non-Small-Cell Lung Cancer Cell Line A549 Proliferation by Interfering with Heme Oxygenase and Glutathione Systems

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 917
Author(s):  
Valeria Sorrenti ◽  
Agata Grazia D’Amico ◽  
Ignazio Barbagallo ◽  
Valeria Consoli ◽  
Salvo Grosso ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Line ◽  
Heme Oxygenase ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Nsclc Cell ◽  
Antioxidant Systems ◽  
Nsclc Cell Line ◽  
Small Cell Lung

In order to maintain redox homeostasis, non-small-cell lung cancer (NSCLC) increases the activation of many antioxidant systems, including the heme-oxygenase (HO) system. The overexpression of HO-1 has been often associated with chemoresistance and tumor aggressiveness. Our results clearly showed an overexpression of the HO-1 protein in A549 NSCLC cell lines compared to that in non-cancerous cells. Thus, we hypothesized that “off-label” use of tin mesoporphyrin, a well-known HO activity inhibitor clinically used for neonatal hyperbilirubinemia, has potential use as an anti-cancer agent. The pharmacological inhibition of HO activity caused a reduction in cell proliferation and migration of A549. SnMP treatment caused an increase in oxidative stress, as demonstrated by the upregulation of reactive oxygen species (ROS) and the depletion of glutathione (GSH) content. To support these data, Western blot analysis was performed to analyze glucose-6-phosphate dehydrogenase (G6PD), TP53-induced glycolysis and the apoptosis regulator (TIGAR), and the glutamate cysteine ligase catalytic (GCLC) subunit, as they represent the main regulators of the pentose phosphate pathway (PPP) and glutathione synthesis, respectively. NCI-H292, a subtype of the NSCLC cell line, did not respond to SnMP treatment, possibly due to low basal levels of HO-1, suggesting a cellular-dependent antitumorigenic effect. Altogether, our results suggest HO activity inhibition may represent a potential target for selective chemotherapy in lung cancer subtypes.

scholarly journals Small-molecule inhibition of APE1 induces apoptosis, pyroptosis, and necroptosis in non-small cell lung cancer

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Kaili Long ◽  
Lili Gu ◽  
Lulu Li ◽  
Ziyu Zhang ◽  
Enjie Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Small Molecule ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Nsclc Cell ◽  
Molecular Compound ◽  
Small Cell Lung

AbstractApurinic/apyrimidinic endonuclease 1 (APE1) plays a critical role in the base excision repair (BER) pathway, which is responsible for the excision of apurinic sites (AP sites). In non-small cell lung cancer (NSCLC), APE1 is highly expressed and associated with poor patient prognosis. The suppression of APE1 could lead to the accumulation of unrepaired DNA damage in cells. Therefore, APE1 is viewed as an important marker of malignant tumors and could serve as a potent target for the development of antitumor drugs. In this study, we performed a high-throughput virtual screening of a small-molecule library using the three-dimensional structure of APE1 protein. Using the AP site cleavage assay and a cell survival assay, we identified a small molecular compound, NO.0449-0145, to act as an APE1 inhibitor. Treatment with NO.0449-0145 induced DNA damage, apoptosis, pyroptosis, and necroptosis in the NSCLC cell lines A549 and NCI-H460. This inhibitor was also able to impede cancer progression in an NCI-H460 mouse model. Moreover, NO.0449-0145 overcame both cisplatin- and erlotinib-resistance in NSCLC cell lines. These findings underscore the importance of APE1 as a therapeutic target in NSCLC and offer a paradigm for the development of small-molecule drugs that target key DNA repair proteins for the treatment of NSCLC and other cancers.

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