Mefloquine HCl promotes DNA repair and alleviates radiation-induced lung epithelial cell injury

doi:10.12122/j.issn.1673-4254.2026.03.03

Abstract

Abstract:

Objective To investigate the protective effect of mefloquine HCl (MQ) against X-ray irradiation-induced DNA damage in lung epithelial cells. Methods Human lung epithelial cells (BEAS-2B) were divided into blank control group, irradiation group, and irradiation+MQ treatment group. The effects of MQ on cell proliferation and radiosensitivity after X-ray irradiation were assessed using CCK-8 assay, EdU-488 assay, and colony formation assay. Apoptosis and cell cycle distribution of BEAS-2B cells with different treatments were detected by flow cytometry. The effect of MQ in promoting DNA double-strand break (DSB) repair was observed using immunofluorescence staining and comet assay, and the molecule ar mechanism was explored using Western blotting, qPCR, and luciferase reporter assays. Results MQ at 0-10 μmol/L did not significantly affect BEAS-2B cell viability. Compared to the irradiated cells, treatment with 0-10 μmol/L MQ enhanced the cell viability, and the effect was the most conspicuous at 10 μmol/L. MQ treatment obviously promoted proliferation and increased clonogenic survival rate of irradiated BEAS-2B cells while reducing their radiosensitivity, and significantly lowered cell apoptosis rate following the irradiation. Cell cycle analysis revealed that MQ alleviated G2/M phase arrest induced by irradiation, and comet assay and immunofluorescence staining showed reduced comet tail moment and γH2AX foci formation in irradiation+MQ group. Western blotting and qPCR demonstrated that MQ treatment for 48 h significantly increased CtIP promoter activity and upregulated CtIP expressions at both the mRNA and protein levels. Conclusion MQ promotes DSB repair in BEAS-2B cells by upregulating CtIP expression and may thus alleviate radiation-induced lung epithelial cell injury.

Key words: mefloquine HCl, radiation-induced lung injury, DNA damage, DNA double-strand break repair

Yan ZHANG, Qingqiu WEN, Haibo HUANG, Meijuan ZHOU, Jianyu WANG. Mefloquine HCl promotes DNA repair and alleviates radiation-induced lung epithelial cell injury[J]. Journal of Southern Medical University, 2026, 46(3): 497-504.

Figures/Tables 5

Fig.1 Effects of different concentrations of MQ on cell viability and HR repair efficiency. A: Cell viability curve. *P<0.05, **P<0.01 vs 0 μmol/L. B: Effect of MQ on HR repair efficiency. C: Effect of MQ on cell viability after irradiation. Data are presented as Mean±SD (n=3). *P<0.05.

Fig.2 Effects of MQ on proliferation and colony formation capacity of X-ray-irradiated BEAS-2B cells. A: Cell proliferation after irradiation (Original magnification: ×50); B: BEAS-2B colony formation diagram. C, D: Statistical analysis diagrams. Data are presented as Mean±SD (n=3). *P<0.05, **P<0.01, ***P<0.001.

Fig.3 Flow cytometry analysis of the effects of MQ on apoptosis and cell cycle in X-ray-irradiated BEAS-2B cells. A, B: Apoptosis analysis by flow cytometry and statistical data. C. Statistical analysis of cell cycle. Data are presented as Mean±SD (n=3). *P<0.05.

Fig.4 Effect of MQ on DNA double-strand break (DSB) repair following irradiation. A, B: Comet assay images and statistical analysis of irradiated BEAS-2B cells (×100). C, D: Immunofluorescence staining and quantification of γH2AX foci in BEAS-2B cells after irradiation (×50). Data are presented as Mean±SD (n=3). *P<0.05.

Fig.5 Effect of MQ on CtIP protein and mRNA levels. A: Protein expression of CtIP after MQ treatment. B: mRNA level of CtIP after MQ treatment. C: Effect of MQ on CtIP mRNA stability. D: Effect of MQ on CtIP promoter activity. Data are presented as Mean±SD (n=3). **P<0.01, ***P<0.001, ****P<0.0001.

References 30

[1]	Baskar R, Lee KA, Yeo R, et al. Cancer and radiation therapy: current advances and future directions[J]. Int J Med Sci, 2012, 9(3): 193-9. doi：10.7150/ijms.3635
[2]	Zhang K, Yang SH, Zhu Y, et al. Protection against acute radiation-induced lung injury: a novel role for the anti-angiogenic agent Endostar[J]. Mol Med Rep, 2012, 6(2): 309-15. doi：10.3892/mmr.2012.903
[3]	Hanania AN, Mainwaring W, Ghebre YT, et al. Radiation-induced lung injury: assessment and management[J]. Chest, 2019, 156(1): 150-62. doi：10.1016/j.chest.2019.03.033
[4]	Xu TK, Zhang YY, Chang PY, et al. Mesenchymal stem cell-based therapy for radiation-induced lung injury[J]. Stem Cell Res Ther, 2018, 9(1): 18. doi：10.1186/s13287-018-0776-6
[5]	Zhen S, Qiang R, Lu JJ, et al. TGF-β1-based CRISPR/Cas9 gene therapy attenuates radiation-induced lung injury[J]. Curr Gene Ther, 2022, 22(1): 59-65. doi：10.2174/1566523220666201230100523
[6]	Beach TA, Groves AM, Williams JP, et al. Modeling radiation-induced lung injury: lessons learned from whole Thorax irradiation[J]. Int J Radiat Biol, 2020, 96(1): 129-44. doi：10.1080/09553002.2018.1532619
[7]	Wei YY, Gong YQ, Wei S, et al. Protection of the hematopoietic system against radiation-induced damage: drugs, mechanisms, and developments[J]. Arch Pharm Res, 2022, 45(8): 558-71. doi：10.1007/s12272-022-01400-7
[8]	Dobbs LG, Johnson MD, Vanderbilt J, et al. The great big alveolar TI cell: evolving concepts and paradigms[J]. Cell Physiol Biochem, 2010, 25(1): 55-62. doi：10.1159/000272063
[9]	Chen FQ, Zhao WN, Du CH, et al. Bleomycin induces senescence and repression of DNA repair via downregulation of Rad51[J]. Mol Med, 2024, 30(1): 54. doi：10.1186/s10020-024-00821-y
[10]	Du J, Chen FQ, Du CH, et al. Amodiaquine ameliorates stress-induced premature cellular senescence via promoting SIRT1-mediated HR repair[J]. Cell Death Discov, 2024, 10(1): 434. doi：10.1038/s41420-024-02201-1
[11]	Arroyo-Hernández M, Maldonado F, Lozano-Ruiz F, et al. Radiation-induced lung injury: current evidence[J]. BMC Pulm Med, 2021, 21(1): 9. doi：10.1186/s12890-020-01376-4
[12]	Zhou SH, Zhu JJ, Zhou PK, et al. Alveolar type 2 epithelial cell senescence and radiation-induced pulmonary fibrosis[J]. Front Cell Dev Biol, 2022, 10: 999600. doi：10.3389/fcell.2022.999600
[13]	Dasgupta Q, Jiang A, Wen AM, et al. A human lung alveolus-on-a-chip model of acute radiation-induced lung injury[J]. Nat Commun, 2023, 14(1): 6506. doi：10.1038/s41467-023-42171-z
[14]	Kim H, Park SH, Han SY, et al. LXA₄-FPR2 signaling regulates radiation-induced pulmonary fibrosis via crosstalk with TGF‑β/Smad signaling[J]. Cell Death Dis, 2020, 11(8): 653. doi：10.1038/s41419-020-02846-7
[15]	Mu JY, Israili ZH, Dayton PG. Studies of the disposition and metabolism of mefloquine HCl (WR 142, 490), a quinolinemethanol antimalarial, in the rat. Limited studies with an analog, WR 30, 090[J]. Drug Metab Dispos, 1975, 3(3): 198-210. doi：10.1016/s0090-9556(25)05714-9
[16]	Lang FC, Cornwell JA, Kaur K, et al. Abrogation of the G2/M checkpoint as a chemosensitization approach for alkylating agents[J]. Neuro Oncol, 2024, 26(6): 1083-96. doi：10.1093/neuonc/noad252
[17]	Yao YH, Qiu XN, Chen M, et al. LKB1 mutations enhance radiosensitivity in non-small cell lung cancer cells by inducing G2/M cell cycle phase arrest[J]. Curr Mol Med, 2025, 25(3): 353-60. doi：10.2174/0115665240280822231221060656
[18]	Bunting SF, Nussenzweig A. End-joining, translocations and cancer[J]. Nat Rev Cancer, 2013, 13(7): 443-54. doi：10.1038/nrc3537
[19]	Zhou FY, Waterman DP, Ashton M, et al. Prolonged cell cycle arrest in response to DNA damage in yeast requires the maintenance of DNA damage signaling and the spindle assembly checkpoint[J]. eLife, 2024, 13: RP94334. doi：10.7554/elife.94334.3.sa0
[20]	Chien TM, Yang CW, Yen CH, et al. Excavatolide C/cisplatin combination induces antiproliferation and drives apoptosis and DNA damage in bladder cancer cells[J]. Arch Toxicol, 2024, 98(5): 1543-60. doi：10.1007/s00204-024-03699-1
[21]	Ciccia A, Elledge SJ. The DNA damage response: making it safe to play with knives[J]. Mol Cell, 2010, 40(2): 179-204. doi：10.1016/j.molcel.2010.09.019
[22]	Chapman JR, Taylor MRG, Boulton SJ. Playing the end game: DNA double-strand break repair pathway choice[J]. Mol Cell, 2012, 47(4): 497-510. doi：10.1016/j.molcel.2012.07.029
[23]	Liu T, Huang J. DNA end resection: facts and mechanisms[J]. Genomics Proteomics Bioinformatics, 2016, 14(3): 126-30. doi：10.1016/j.gpb.2016.05.002
[24]	Lamarche BJ, Orazio NI, Weitzman MD. The MRN complex in double-strand break repair and telomere maintenance[J]. FEBS Lett, 2010, 584(17): 3682-95. doi：10.1016/j.febslet.2010.07.029
[25]	Clarke TL, Cho HM, Ceppi I, et al. ZNF280A links DNA double-strand break repair to human 22q11.2 distal deletion syndrome[J]. Nat Cell Biol, 2025, 27(6): 1006-20. doi：10.1038/s41556-025-01674-1
[26]	Jiang YN, Yam JC, Tham CC, et al. RB regulates DNA double strand break repair pathway choice by mediating CtIP dependent end resection[J]. Int J Mol Sci, 2020, 21(23): 9176. doi：10.3390/ijms21239176
[27]	Xie DF, Huang Q, Zhou PK. Drug discovery targeting post-translational modifications in response to DNA damages induced by space radiation[J]. Int J Mol Sci, 2023, 24(8): 7656. doi：10.3390/ijms24087656
[28]	Yadav N, Dwivedi A, Mujtaba SF, et al. Photosensitized mefloquine induces ROS-mediated DNA damage and apoptosis in keratinocytes under ambient UVB and sunlight exposure[J]. Cell Biol Toxicol, 2014, 30(5): 253-68. doi：10.1007/s10565-014-9280-7
[29]	Yan KH, Yao CJ, Hsiao CH, et al. Mefloquine exerts anticancer activity in prostate cancer cells via ROS-mediated modulation of Akt, ERK, JNK and AMPK signaling[J]. Oncol Lett, 2013, 5(5): 1541-5. doi：10.3892/ol.2013.1211
[30]	Martins AC, Paoliello MMB, Docea AO, et al. Review of the mechanism underlying mefloquine-induced neurotoxicity[J]. Crit Rev Toxicol, 2021, 51(3): 209-16. doi：10.1080/10408444.2021.1901258