Inhibition of DNA‑PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC

Chi, Pan; Duan, Huijie; Wu, Yinan; Zhu, Chunpeng; Yi, Chenghao; Yin, Dong; Lu, Demin; Guo, Cheng; Wu, Deqi; Wang, Yanyan; Fu, Xianhua; Xu, Jing; Chen, Yiding; Luo, Meng; Tian, Wei; Xu, Wenhong; Zhang, Suzhan; Huang, Jianjin

doi:10.3892/ijo.2020.5103

Cited by 3 publications

(3 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…AZD7648, a highly-potent and specific DNA-PK inhibitor, sensitized the anti-NSCLC cell activity by radiation, chemotherapy and olaparib [ 36 ]. Pan et al, have shown that gefitinib could selectively inhibit EGFR and decrease DNA-PK activity, thereby enhancing cytotoxicity by cisplatin against NSCLC cells [ 37 ]. Liang et al, reported that DNA-PK inhibition could sensitize NSCLC cells to a third-generation EGFR blocker osimertinib [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

An mTOR and DNA-PK dual inhibitor CC-115 hinders non-small cell lung cancer cell growth

Chen

Zhao

et al. 2022

Cell Death Discov.

View full text Add to dashboard Cite

Molecularly-targeted agents are still urgently needed for better non-small cell lung cancer (NSCLC) therapy. CC-115 is a potent DNA-dependent protein kinase (DNA-PK) and mammalian target of rapamycin (mTOR) dual blocker. We evaluated its activity in different human NSCLC cells. In various primary human NSCLC cells and A549 cells, CC-115 potently inhibited viability, cell proliferation, cell cycle progression, and hindered cell migration/invasion. Apoptosis was provoked in CC-115-stimulated NSCLC cells. The dual inhibitor, however, was unable to induce significant cytotoxic and pro-apoptotic activity in the lung epithelial cells. In primary NSCLC cells, CC-115 blocked activation of mTORC1/2 and DNA-PK. Yet, CC-115-induced primary NSCLC cell death was more potent than combined inhibition of DNA-PK plus mTOR. Further studies found that CC-115 provoked robust oxidative injury in primary NSCLC cells, which appeared independent of mTOR-DNA-PK dual blockage. In vivo studies showed that CC-115 oral administration in nude mice remarkably suppressed primary NSCLC cell xenograft growth. In CC-115-treated NSCLC xenograft tissues, mTOR-DNA-PK dual inhibition and oxidative injury were detected. Together, CC-115 potently inhibits NSCLC cell growth.

show abstract

Section: Discussionmentioning

confidence: 99%

An mTOR and DNA-PK dual inhibitor CC-115 hinders non-small cell lung cancer cell growth

Chen

Zhao

et al. 2022

Cell Death Discov.

View full text Add to dashboard Cite

show abstract

“…Whereas, the widespread resistance to cisplatin renders malignant cells less susceptible to the antiproliferative and cytotoxic effects of the drug [2]. Through combination with third generation cytotoxic agents such as gemcitabine, taxanes or ge tinib could signi cantly improve the curative effect of cisplatin, however, these cytotoxic drugs are often associated with severe side effects, and their clinical applications are limited seriously [3][4][5]. Therefore, it is urgent to nd adjuvant drugs which can be used in combination with cisplatin, enhance its e cacy, and decrease its side effects [6].…”

Section: Introductionmentioning

confidence: 99%

Effect of dihydromyricetin combined with cisplatin on treatment of lung cancer cell A549

Hao

Pang

Zhu

et al. 2023

Preprint

View full text Add to dashboard Cite

Objective Chemotherapy resistance and side effects are important reasons for the failure of lung cancer treatment. Therefore, finding new sensitizers for chemotherapeutic drugs is an urgent problem to be solved.Method In this study, A549 cells were given different pharmacological interventions, including control, cisplatin, DMY and the combination of cisplatin and DMY. The level of cell proliferation and apoptosis were detected by MTT assay and Flow cytometry AV/PI double staining. Transwell assay was adopted to detect the ability of migration and invasion of A549 cells. Western blot analyzed the expression of protein about proliferation, apoptosis, migration, and invasion.Results The present study denoted that DMY strengthened the effect of cisplatin on the inhibition of proliferation in lung cancer A549 cells. Meanwhile, DMY promoted cisplatin induced apoptosis of A549 cells. Further, DMY combined with cisplatin can synergistically inhibit the migration and invasion of A549 cells. Western blotting results showed that the expression of E-cadherin was significantly increased in the combination group compared to cisplatin group, while, the expression of N-cadherin, matrix metalloproteinase MMP 2, MMP 9 and Smads proteins (p-SMAD 3, t-SMAD 3, t-SMAD 4), were significantly decreased in the combination group.Conclusion Low dosage of DMY can significantly enhance the effect of cisplatin treatment in lung cancer cells, and its mechanism may be related to the induction of apoptosis, inhibition of proliferation, migration and invasion, which is expected to be a low-toxic and efficient chemosensitizer for lung cancer treatment.

show abstract

“…Gefitinib, which is one of the epidermal growth factor receptor (EGFR) small molecule tyrosine kinase inhibitor tyrosine kinase inhibitors (TKIs), is widely used for patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations 20 , including exon 19 deletion and exon 21 L858R mutation. However, numerous patients cannot benefit or continue to benefit from EGFR-TKI monotherapy due to primary and secondary drug resistance after a period of treatment 21 . CSCs were found enriched and the EGFR mutant cells acquired resistance during the treatment with EGFR inhibitors 22 .…”

Section: Introductionmentioning

confidence: 99%

The efficacy of PI3Kγ and EGFR inhibitors on the suppression of the characteristics of cancer stem cells

Afify

et al. 2022

Sci Rep

View full text Add to dashboard Cite

Cancer stem cells (CSCs) are capable of continuous proliferation, self-renewal and are proposed to play significant roles in oncogenesis, tumor growth, metastasis and cancer recurrence. We have established a model of CSCs that was originally developed from mouse induced pluripotent stem cells (miPSCs) by proposing miPSCs to the conditioned medium (CM) of cancer derived cells, which is a mimic of carcinoma microenvironment. Further research found that not only PI3K-Akt but also EGFR signaling pathway was activated during converting miPSCs into CSCs. In this study, we tried to observe both of PI3Kγ inhibitor Eganelisib and EGFR inhibitor Gefitinib antitumor effects on the models of CSCs derived from miPSCs (miPS-CSC) in vitro and in vivo. As the results, targeting these two pathways exhibited significant inhibition of cell proliferation, self-renewal, migration and invasion abilities in vitro. Both Eganelisib and Gefitinib showed antitumor effects in vivo while Eganelisib displayed more significant therapeutic efficacy and less side effects than Gefitinib on all miPS-CSC models. Thus, these data suggest that the inhibitiors of PI3K and EGFR, especially PI3Kγ, might be a promising therapeutic strategy against CSCs defeating cancer in the near future.

show abstract

Inhibition of DNA‑PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC

Cited by 3 publications

References 63 publications

An mTOR and DNA-PK dual inhibitor CC-115 hinders non-small cell lung cancer cell growth

An mTOR and DNA-PK dual inhibitor CC-115 hinders non-small cell lung cancer cell growth

Effect of dihydromyricetin combined with cisplatin on treatment of lung cancer cell A549

The efficacy of PI3Kγ and EGFR inhibitors on the suppression of the characteristics of cancer stem cells

Contact Info

Product

Resources

About