DNA-PK inhibition by M3814 enhances chemosensitivity in non-small cell lung cancer
| العنوان: | DNA-PK inhibition by M3814 enhances chemosensitivity in non-small cell lung cancer |
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| المؤلفون: | Siyuan Chen, Xiawei Wei, Manni Wang, Yuquan Wei |
| المصدر: | Acta Pharmaceutica Sinica. B Acta Pharmaceutica Sinica B, Vol 11, Iss 12, Pp 3935-3949 (2021) |
| بيانات النشر: | Elsevier, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Senescence, Paclitaxel, DNA repair, NHEJ, non homologous end joining, medicine.medical_treatment, LCLC, large-cell carcinoma, RM1-950, Chemosensitization, DDR, DNA damage response, chemistry.chemical_compound, Non-small cell lung cancer, DNA-PK, DNA-dependent protein kinase, NSCLC, non-small cell lung cancer, medicine, Cytotoxic T cell, General Pharmacology, Toxicology and Pharmaceutics, Lung cancer, Adverse effect, DSB, DNA double-strand breaks, Etoposide, DNA-PKcs, DNA-dependent protein kinase catalytic subunit, Chemotherapy, business.industry, LADC, lung adenocarcinoma, medicine.disease, LSCC, lung squamous cell carcinoma, respiratory tract diseases, M3814, dsDNA, double strand DNA, chemistry, DNA-dependent protein kinase, Cancer research, Original Article, Cell senescence, Therapeutics. Pharmacology, HR, homologous recombination, business, IHC, immunohistochemistry, medicine.drug |
| الوصف: | A significant proportion of non-small cell lung cancer (NSCLC) patients experience accumulating chemotherapy-related adverse events, motivating the design of chemosensitizating strategies. The main cytotoxic damage induced by chemotherapeutic agents is DNA double-strand breaks (DSB). It is thus conceivable that DNA-dependent protein kinase (DNA-PK) inhibitors which attenuate DNA repair would enhance the anti-tumor effect of chemotherapy. The present study aims to systematically evaluate the efficacy and safety of a novel DNA-PK inhibitor M3814 in synergy with chemotherapies on NSCLC. We identified increased expression of DNA-PK in human NSCLC tissues which was associated with poor prognosis. M3814 potentiated the anti-tumor effect of paclitaxel and etoposide in A549, H460 and H1703 NSCLC cell lines. In the four combinations based on two NSCLC xenograft models and two chemotherapy, we also observed tumor regression at tolerated doses in vivo. Moreover, we identified a P53-dependent accelerated senescence response by M3814 following treatment with paclitaxel/etoposide. The present study provides a theoretical basis for the use of M3814 in combination with paclitaxel and etoposide in clinical practice, with hope to aid the optimization of NSCLC treatment. Graphical abstract This study elucidates the chemosensitization effect of M3814, a new-generation DNA-PK inhibitor on non-small cell lung cancer, providing theoretical bases for the clinical application of M3814-chemotherapy synergy.Image 1 |
| اللغة: | English |
| تدمد: | 2211-3843 2211-3835 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::48576014833ff0883918307b9873dc5eTest http://europepmc.org/articles/PMC8727896Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....48576014833ff0883918307b9873dc5e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 22113843 22113835 |
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