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Downregulation of breast cancer resistance protein by long-term fractionated radiotherapy sensitizes lung adenocarcinoma to SN-38

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Summary

Chemotherapy is usually the subsequent treatment for non-small cell lung cancer patients with acquired radioresistance after long-term fractionated radiotherapy. However, few studies have focused on the selection of chemotherapeutic drugs to treat lung adenocarcinoma patients with radioresistance. Our study compared the sensitivity changes of lung adenocarcinoma cells to conventional chemotherapeutic drugs under radioresistant circumstances by using three lung adenocarcinoma cell models, which were irradiated with fractionated X-rays at a total dose of 60 Gy. The results showed that the toxicities of paclitaxel, docetaxel and SN-38 were increased in radioresistant cells. The IC50 values of docetaxel and SN-38 decreased 0 ~ 3 times and 3 ~ 36 times in radioresistant cells, respectively. Notably, the A549 radioresistant cells were approximately 36 times more sensitive to SN-38 than the parental cells. Further results revealed that the downregulation of the efflux transporter BCRP by long-term fractionated irradiation was an important factor contributing to the increased cytotoxicity of SN-38. In addition, the reported miRNAs and transcriptional factors that regulate BCRP did not participate in the downregulation. In conclusion, these results presented important data on the sensitivity changes of lung adenocarcinoma cells to chemotherapeutic drugs after acquiring radioresistance and suggested that irinotecan (the prodrug of SN-38) might be a promising drug candidate for lung adenocarcinoma patients with acquired radioresistance.

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Acknowledgements

The authors thank Prof. Huidi Jiang and Prof. Su Zeng from the College of Pharmaceutical Sciences, Zhejiang University, for their kind advice and help.

Availability of data and material

We declared that materials described in the manuscript, including all relevant raw data, will be freely available to any scientist wishing to use them for non-commercial purposes, without breaching participant confidentiality.

Funding

The work was supported by the Zhejiang Provincial Natural Science Foundation of China under Grant No. LQ19H310001, Zhejiang Provincial Medicine and Health Science Foundation (grant No. 2020RC027) and National Natural Scientific Foundation of China (81803631, 81773242).

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Authors and Affiliations

  1. Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China

    Yuqing Wang, Jingjing Zhang, Zhiyuan Ma, Shenglin Ma & Shirong Zhang

  2. Translational Medicine Research Center, Hangzhou First People’s Hospital, Nanjing Medical University, Nanjing, 211166, China

    Jie Huang

  3. The fourth College of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China

    Qiong Wu

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  1. Yuqing Wang
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Contributions

Shirong Zhang, Shenglin Ma and Yuqing Wang conceived and designed the study. Yuqing Wang, Jie Huang, Qiong Wu and Jingjing Zhang performed the experiments. Yuqing Wang wrote the paper. Shirong Zhang, Shenglin Ma and Zhiyuan Ma reviewed and edited the manuscript.

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Correspondence to Shenglin Ma or Shirong Zhang.

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Yuqing Wang declares that she has no conflict of interest. Jie Huang declares that he has no conflict of interest. Qiong Wu declares that she has no conflict of interest. Jingjing Zhang declares that she has no conflict of interest. Zhiyuan Ma declares that she has no conflict of interest. Shenglin Ma declares that he has no conflict of interest. Shirong Zhang declares that she has no conflict of interest.

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Wang, Y., Huang, J., Wu, Q. et al. Downregulation of breast cancer resistance protein by long-term fractionated radiotherapy sensitizes lung adenocarcinoma to SN-38. Invest New Drugs 39, 458–468 (2021). https://doi.org/10.1007/s10637-020-01003-3

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