Citation: Guizhen Zhu, Yaoyao Zhao, Wenmei Zhang, Yuanyuan Wu, Yuanxing Liu, Guangsheng Guo, Xiayan Wang, Zhihong Liu. Single-cell mass spectrometry studies of drug metabolism heterogeneity and primary resistance to gefitinib in non-small cell lung cancer cells[J]. Chinese Chemical Letters, ;2024, 35(2): 108466. doi: 10.1016/j.cclet.2023.108466 shu

Single-cell mass spectrometry studies of drug metabolism heterogeneity and primary resistance to gefitinib in non-small cell lung cancer cells

Guizhen Zhu ^a ,
Yaoyao Zhao ^{a, *,} ,
Wenmei Zhang ^a ,
Yuanyuan Wu ^a ,
Yuanxing Liu ^a ,
Guangsheng Guo ^{a, b} ,
Xiayan Wang ^a ,
Zhihong Liu ^{c, *,}

a.
Center of Excellence for Environmental Safety and Biological Effects, Beijing Key Laboratory for Green Catalysis and Separation, Department of Chemistry, Beijing University of Technology, Beijing 100124, China
b.
Minzu University of China, Beijing 100081, China
c.
Key Laboratory for the Synthesis and Application of Organic Functional Molecules, College of Health Science and Engineering, Hubei University, Wuhan 430062, China

zhaoyaoyao@bjut.edu.cn

zhhliu@whu.edu.cn

Received Date: 9 March 2023
Revised Date: 23 March 2023
Accepted Date: 16 April 2023
Available Online: 21 April 2023

Figures(6)

Patients with epidermal growth factor receptor (EGFR) wild-type non-small cell lung cancer (NSCLC) often show primary resistance to gefitinib therapy. It is thus necessary to study the metabolism of gefitinib in NSCLC cells to comprehensively reveal the reasons for the primary resistance of tumors. Herein, we develop a platform for studying drug metabolism heterogeneity based on single-cell mass spectrometry (sDMH-scMS) by integrating living-cell electrolaunching ionization MS (ILCEI-MS) and high-performance liquid chromatography-MS (HPLC-MS) analysis, and the primary resistance of NSCLC cells to gefitinib was studied using this platform. The ILCEI-MS analysis showed that approximately 11.9% of NSCLC single cells contained the gefitinib metabolite M11; HPLC-MS detection diluted the intensity of M11 in subpopulations and concealed the heterogeneity of drug metabolism in tumor single cells. The intensity of gefitinib in EGFR wild-type A549 cells was markedly lower than in mutant PC9 cells, and the intensity of gefitinib metabolites was significantly higher than in PC9 cells, suggesting that the primary resistance of NSCLC cells is related to gefitinib metabolism. Moreover, the combination of gefitinib and the drug-metabolizing enzyme inhibitor α-naphthoflavone was shown to overcome the primary resistance of the NSCLC cells. Overall, the results of this study are expected to be applicable for clinical drug resistance diagnosis and treatment at the single-cell level.
- Single-cell mass spectrometry,
- Drug metabolism,
- Non-small cell lung cancer,
- Gefitinib,
- Primary resistance
1. [1]
  I. Solassol, F. Pinguet, X. Quantin, Biomolecules 9 (2019) 668. doi: 10.3390/biom9110668
2. [2]
  J.G. Paez, P.A. Janne, J.C. Lee, et al., Science 304 (2004) 1497–1500. doi: 10.1126/science.1099314
3. [3]
  H. -. R. Kim, J.C. Lee, Y. -. C. Kim, et al., Lung Cancer 83 (2014) 252–258. doi: 10.1016/j.lungcan.2013.11.008
4. [4]
  E.N. Imyanitov, A.G. Iyevleva, E.V. Levchenko, Crit. Rev. Oncol. Hematol. 157 (2021) 103194. doi: 10.1016/j.critrevonc.2020.103194
5. [5]
  J.H. Baek, J.M. Sun, Y.J. Min, et al., Lung Cancer 87 (2015) 148–154. doi: 10.1016/j.lungcan.2014.11.013
6. [6]
  E. Tsvetkova, G.D. Goss, Curr. Oncol. 19 (2012) S45–S51. doi: 10.3747/co.19.1113
7. [7]
  H. Linardou, I.J. Dahabreh, D. Bafaloukos, et al., Nat. Rev. Clin. Oncol. 6 (2009) 352–366. doi: 10.1038/nrclinonc.2009.62
8. [8]
  P.I. Poulikakos, C. Zhang, G. Bollag, et al., Nature 464 (2010) 427–430. doi: 10.1038/nature08902
9. [9]
  C. Yamamoto, Y. Basaki, A. Kawahara, et al., Cancer Res. 70 (2010) 8715–8725. doi: 10.1158/0008-5472.CAN-10-0043
10. [10]
  R.R. Alfieri, M. Galetti, S. Tramonti, et al., Mol. Cancer 10 (2011) 143. doi: 10.1186/1476-4598-10-143
11. [11]
  L. Huang, L. Fu, Acta Pharm. Sin. B 5 (2015) 390–401. doi: 10.1016/j.apsb.2015.07.001
12. [12]
  C. Hegedus, K. Truta-Feles, G. Antalffy, et al., Biochem. Pharmacol. 84 (2012) 260–267. doi: 10.1016/j.bcp.2012.04.010
13. [13]
  J. Rawluk, C.F. Waller, Gefitinib, in: U. Martens (Ed.), Small Molecules in Oncology, Recent Results in Cancer Research, Springer, Cham, 2018, pp. 235–246.
14. [14]
  C. Zhao, N. Zheng, F. Yang, et al., Biomed. Chromatogr. 33 (2019) e4638. doi: 10.1002/bmc.4638
15. [15]
  D. McKillop, A.D. McCormick, G.S. Miles, et al., Xenobiotica 34 (2004) 983–1000. doi: 10.1080/02772240400015222
16. [16]
  D. McKillop, A.D. McCormick, A. Millar, et al., Xenobiotica 35 (2005) 39–50. doi: 10.1080/00498250400026464
17. [17]
  X. Liu, Y. Lu, X. Guan, et al., Biochem. Pharmacol. 97 (2015) 111–121.
18. [18]
  D. McKillop, M. Hutchison, E.A. Partridge, et al., Xenobiotica 34 (2004) 917–934. doi: 10.1080/00498250400009171
19. [19]
  C. Wang, J. Zhang, S. Zhou, et al., PLoS ONE 15 (2020) e0236523. doi: 10.1371/journal.pone.0236523
20. [20]
  J. Li, M. Zhao, P. He, et al., Clin. Cancer Res. 13 (2007) 3731–3737. doi: 10.1158/1078-0432.CCR-07-0088
21. [21]
  C. Zhao, S.Y. Han, P.P. Li, Curr. Drug Deliv. 14 (2017) 282–288. doi: 10.3390/ma10030282
22. [22]
  G. Zhu, Y. Shao, Y. Liu, et al., Trac-Trends Anal. Chem. 143 (2021) 116351. doi: 10.1016/j.trac.2021.116351
23. [23]
  L. Zhang, A. Vertes, Angew. Chem. Int. Ed. 57 (2018) 4466–4477. doi: 10.1002/anie.201709719
24. [24]
  Y. Liu, Y. Mi, T. Mueller, et al., Nat. Biotechnol. 37 (2019) 314–322. doi: 10.1038/s41587-019-0037-y
25. [25]
  U. Ben-David, B. Siranosian, G. Ha, et al., Nature 560 (2018) 325–330. doi: 10.1038/s41586-018-0409-3
26. [26]
  Y. Shen, B.U.S. Schmidt, H. Kubitschke, et al., Cancer Converg. 4 (2020) 1. doi: 10.1186/s41236-020-0010-1
27. [27]
  N. Pan, S.J. Standke, N.R. Kothapalli, et al., Anal. Chem. 91 (2019) 9018–9024. doi: 10.1021/acs.analchem.9b01311
28. [28]
  M. Sun, X. Chen, Z. Yang, Anal. Chim. Acta 1206 (2022) 339761. doi: 10.1016/j.aca.2022.339761
29. [29]
  Z. Shen, H. Zhao, H. Yao, et al., Chem. Sci. 13 (2022) 1641–1647. doi: 10.1039/d1sc06366a
30. [30]
  S. Xu, M. Liu, Y. Bai, et al., Angew. Chem. Int. Ed. 60 (2021) 1806–1812. doi: 10.1002/anie.202009682
31. [31]
  X. Chen, Z. Peng, Z. Yang, Chem. Sci. 13 (2022) 6687–6695. doi: 10.1039/d2sc02298b
32. [32]
  M. Zhuang, Z. Hou, P. Chen, et al., Chem. Sci. 11 (2020) 7308–7312. doi: 10.1039/d0sc00259c
33. [33]
  W. Zhang, N. Li, L. Lin, et al., Small 15 (2019) 1903402.
34. [34]
  G. Zhu, W. Zhang, Y. Zhao, et al., Anal. Chem. 95 (2023) 4712–4720. doi: 10.1021/acs.analchem.2c05351
35. [35]
  C. Wang, W. Hu, L. Guan, et al., Chin. Chem. Lett. 33 (2022) 2883–2892. doi: 10.1016/j.cclet.2021.10.006
36. [36]
  Y. Shao, Y. Zhou, Y. Liu, et al., Chem. Sci. 13 (2022) 8065–8073. doi: 10.1039/d2sc02569h
37. [37]
  L. Wang, W. Peng, T. Wu, et al., Cell Death Discov. 4 (2018) 84. doi: 10.1038/s41420-018-0086-x
38. [38]
  X. Li, T.M. Kamenecka, M.D. Cameron, Chem. Res. Toxicol. 22 (2009) 1736–1742. doi: 10.1021/tx900256y
1. [1]
  Zhi Li , Shuya Pan , Yuan Tian , Shaowei Liu , Weifeng Wei , Jinlin Wang , Tianfeng Chen , Ling Wang . Selenium nanoparticles enhance the chemotherapeutic efficacy of pemetrexed against non-small cell lung cancer. Chinese Chemical Letters, 2024, 35(12): 110018-. doi: 10.1016/j.cclet.2024.110018
2. [2]
  Haiyan Lu , Jiayue Ye , Yiping Wei , Hua Zhang , Konstantin Chingin , Vladimir Frankevich , Huanwen Chen . Tracing molecular margins of lung cancer by internal extractive electrospray ionization mass spectrometry. Chinese Chemical Letters, 2025, 36(2): 110077-. doi: 10.1016/j.cclet.2024.110077
3. [3]
  Shaoqing Du , Xinyong Liu , Xueping Hu , Peng Zhan . Targeting novel sites represents an effective strategy for combating drug resistance. Chinese Chemical Letters, 2025, 36(1): 110378-. doi: 10.1016/j.cclet.2024.110378
4. [4]
  Jing Chen , Peisi Xie , Pengfei Wu , Yu He , Zian Lin , Zongwei Cai . MALDI coupled with laser-postionization and trapped ion mobility spectrometry contribute to the enhanced detection of lipids in cancer cell spheroids. Chinese Chemical Letters, 2024, 35(4): 108895-. doi: 10.1016/j.cclet.2023.108895
5. [5]
  Liping Zhao , Xixi Guo , Zhimeng Zhang , Xi Lu , Qingxuan Zeng , Tianyun Fan , Xintong Zhang , Fenbei Chen , Mengyi Xu , Min Yuan , Zhenjun Li , Jiandong Jiang , Jing Pang , Xuefu You , Yanxiang Wang , Danqing Song . Novel berberine derivatives as adjuvants in the battle against Acinetobacter baumannii: A promising strategy for combating multi-drug resistance. Chinese Chemical Letters, 2024, 35(10): 109506-. doi: 10.1016/j.cclet.2024.109506
6. [6]
  Wen Su , Siying Liu , Qingfu Zhang , Zhongyan Zhou , Na Wang , Lei Yue . Temperature-controlled electrospray ionization tandem mass spectrometry study on protein/small molecule interaction. Chinese Chemical Letters, 2025, 36(5): 110237-. doi: 10.1016/j.cclet.2024.110237
7. [7]
  Jiechen Liu , Xiaoguang Li , Ruiyang Xia , Yuqi Wang , Fenghe Zhang , Yongzhi Pang , Qing Li . Efficient suppression of oral squamous cell carcinoma through spatial dimension conversion drug delivery systems-enabled immunomodulatory-photodynamic therapy. Chinese Chemical Letters, 2024, 35(12): 109619-. doi: 10.1016/j.cclet.2024.109619
8. [8]
  Yanhua Chen , Xian Ding , Jun Zhou , Zhaoying Wang , Yunhai Bo , Ying Hu , Qingce Zang , Jing Xu , Ruiping Zhang , Jiuming He , Fen Yang , Zeper Abliz . Plasma metabolomics combined with mass spectrometry imaging reveals crosstalk between tumor and plasma in gastric cancer genesis and metastasis. Chinese Chemical Letters, 2025, 36(1): 110351-. doi: 10.1016/j.cclet.2024.110351
9. [9]
  Keqiang Shi , Xiujuan Hong , Dongyan Xu , Tao Pan , Huiwen Wang , Hongru Feng , Cheng Guo , Yuanjiang Pan . Analysis of RNA modifications in peripheral white blood cells from breast cancer patients by mass spectrometry. Chinese Chemical Letters, 2025, 36(3): 110079-. doi: 10.1016/j.cclet.2024.110079
10. [10]
  Xiaofang Luo , Ye Wu , Xiaokun Zhang , Min Tang , Feiye Ju , Zuodong Qin , Gregory J Duns , Wei-Dong Zhang , Jiang-Jiang Qin , Xin Luan . Peptide-based strategies for overcoming multidrug-resistance in cancer therapy. Chinese Chemical Letters, 2025, 36(1): 109724-. doi: 10.1016/j.cclet.2024.109724
11. [11]
  Yang Liu , Yan Liu , Kaiyin Yang , Zhiruo Zhang , Wenbo Zhang , Bingyou Yang , Hua Li , Lixia Chen . A selective HK2 degrader suppresses SW480 cancer cell growth by degrading HK2. Chinese Chemical Letters, 2024, 35(8): 109264-. doi: 10.1016/j.cclet.2023.109264
12. [12]
  Boran Cheng , Lei Cao , Chen Li , Fang-Yi Huo , Qian-Fang Meng , Ganglin Tong , Xuan Wu , Lin-Lin Bu , Lang Rao , Shubin Wang . Fluorine-doped carbon quantum dots with deep-red emission for hypochlorite determination and cancer cell imaging. Chinese Chemical Letters, 2024, 35(6): 108969-. doi: 10.1016/j.cclet.2023.108969
13. [13]
  Yuanzheng Wang , Chen Zhang , Shuyan Han , Xiaoli Kong , Changyun Quan , Jun Wu , Wei Zhang . Cancer cell membrane camouflaged biomimetic gelatin-based nanogel for tumor inhibition. Chinese Chemical Letters, 2024, 35(11): 109578-. doi: 10.1016/j.cclet.2024.109578
14. [14]
  Yanfei Liu , Yaqin Hu , Yifu Tan , Qiwen Chen , Zhenbao Liu . Tumor acidic microenvironment activatable DNA nanostructure for precise cancer cell targeting and inhibition. Chinese Chemical Letters, 2025, 36(1): 110289-. doi: 10.1016/j.cclet.2024.110289
15. [15]
  Yanjun Cai , Yong Jiang , Yu Chen , Erzhuo Cheng , Yuan Gu , Yuwei Li , Qianqian Liu , Jian Zhang , Jifang Liu , Shisong Han , Bin Yang . Amplifying STING activation and immunogenic cell death by metal-polyphenol coordinated nanomedicines for enhanced cancer immunotherapy. Chinese Chemical Letters, 2025, 36(5): 110437-. doi: 10.1016/j.cclet.2024.110437
16. [16]
  Jianqiu Li , Yi Zhang , Songen Liu , Jie Niu , Rong Zhang , Yong Chen , Yu Liu . Cucurbit[8]uril-based non-covalent heterodimer realized NIR cell imaging through topological transformation from nanowire to nanorod. Chinese Chemical Letters, 2024, 35(10): 109645-. doi: 10.1016/j.cclet.2024.109645
17. [17]
  Lixian Fu , Yiyun Tan , Yue Ding , Weixia Qing , Yong Wang . Water–soluble and polarity–sensitive near–infrared fluorescent probe for long–time specific cancer cell membranes imaging and C. Elegans label. Chinese Chemical Letters, 2024, 35(4): 108886-. doi: 10.1016/j.cclet.2023.108886
18. [18]
  Yihan Zhou , Duo Gao , Yaying Wang , Li Liang , Qingyu Zhang , Wenwen Han , Jie Wang , Chunliu Zhu , Xinxin Zhang , Yong Gan . Worm-like micelles facilitate the intestinal mucus diffusion and drug accumulation for enhancing colorectal cancer therapy. Chinese Chemical Letters, 2024, 35(6): 108967-. doi: 10.1016/j.cclet.2023.108967
19. [19]
  Tong Tong , Lezong Chen , Siying Wu , Zhong Cao , Yuanbin Song , Jun Wu . Establishment of a leucine-based poly(ester amide)s library with self-anticancer effect as nano-drug carrier for colorectal cancer treatment. Chinese Chemical Letters, 2024, 35(12): 109689-. doi: 10.1016/j.cclet.2024.109689
20. [20]
  Yunan Yuan , Zhimin Luo , Jie Chen , Chaoliang He , Kai Hao , Huayu Tian . Constructing thermoresponsive PNIPAM-based microcarriers for cell culture and enzyme-free cell harvesting. Chinese Chemical Letters, 2024, 35(7): 109549-. doi: 10.1016/j.cclet.2024.109549

Get Citation

PDF

XML

Metrics

PDF Downloads(2)
Abstract views(517)
HTML views(19)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142