期刊
ACTA PHARMACEUTICA SINICA B
卷 11, 期 12, 页码 3935-3949出版社
INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
DOI: 10.1016/j.apsb.2021.07.029
关键词
M3814; Paclitaxel; Etoposide; DNA-dependent protein kinase; Non-small cell lung cancer; DNA repair; Cell senescence; Chemosensitization
资金
- National Natural Science Foundation Regional Innovation and Development (China) [U19A2003]
- Excellent Youth Foundation of Sichuan Scientific Committee Grant in China [2019JDJQ008]
The study identified that the DNA-PK inhibitor M3814 enhanced the anti-tumor effect of chemotherapy in NSCLC cell lines, providing a theoretical basis for its potential use in clinical practice to optimize NSCLC treatment.
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. (C) 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
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