Skip to main content
SpringerLink
Log in

FNC inhibits non-small cell lung cancer by activating the mitochondrial apoptosis pathway

  • Research Article
  • Published:
Genes & Genomics Aims and scope Submit manuscript

Abstract

Background

Previously, we published that 4′-azid-2′-deoxy-2′-fluorarabinoside (FNC), a novel cytosine nucleoside analog, has good anti-viral and anti-tumor activity.

Objective

This study aimed to further explore the role and molecular mechanism of FNC in non-small cell lung cancer (NSCLC).

Methods

FNC was tested in the NSCLC H460 cell line, the Lewis mouse model, and the H460 cell xenograft model. The effects of FNC were assessed by cell viability, transwell migration, and wound scratch analyses of cell migration and invasion. Apoptosis was assessed by flow cytometry. Proteins expression was assessed by western blot and immunohistochemistry staining (IHC).

Results

FNC inhibits the proliferation and metastasis of H460 cells in a time- and dose-dependent manner. FNC treatment showed efficacy and low toxicity in the Lewis mouse lung cancer model as well as in the H460 cell xenograft model. Further, FNC induced H460 cell apoptosis through the activation of the mitochondrial pathway. Notably, FNC inhibited invasion by increasing E-cadherin protein and reducing the protein expression of VEGF, MMP-2, MMP-9, and CD31.

Conclusion

FNC inhibits NSCLC by activating the mitochondrial apoptosis pathway and regulating the expressions of multiple proteins related to cell adhesion and invasion, highlighting its potential as an NSCLC therapeutic.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Availability of supporting data

All data and materials are available upon request.

References

  • Balata H, Fong KM, Hendriks LE, Lam S, Ostroff JS, Peled N, Wu N, Aggarwal C (2019) Prevention and early detection for NSCLC: advances in thoracic oncology 2018. J Thorac Oncol 14:1513–1527

    Article  PubMed  Google Scholar 

  • Frezzetti D, Gallo M, Maiello MR, D’Alessio A, Esposito C, Chicchinelli N, Normanno N, De Luca A (2017) VEGF as a potential target in lung cancer. Expert Opin Ther Targets 21:959–966

    Article  CAS  PubMed  Google Scholar 

  • Hata AN, Engelman JA, Faber AC (2015) The BCL2 family: key mediators of the apoptotic response to targeted anticancer therapeutics. Cancer Discov 5:475–487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Herbst RS, Morgensztern D, Boshoff C (2018) The biology and management of non-small cell lung cancer. Nature 553:446–454

    Article  CAS  PubMed  Google Scholar 

  • Inamura K (2017) Lung cancer: understanding its molecular pathology and the 2015 WHO classification. Front Oncol 7:193

    Article  PubMed  PubMed Central  Google Scholar 

  • Jordheim LP, Durantel D, Zoulim F, Dumontet C (2013) Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases. Nat Rev Drug Discov 12:447–464

    Article  CAS  PubMed  Google Scholar 

  • Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ko EC, Raben D, Formenti SC (2018) The Integration of Radiotherapy with Immunotherapy for the treatment of non-small cell lung cancer. Clin Cancer Res 24:5792–5806

    Article  CAS  PubMed  Google Scholar 

  • Larsen BD, Sørensen CS (2017) The caspase-activated DNase: apoptosis and beyond. FEBS J 284:1160–1170

    Article  CAS  PubMed  Google Scholar 

  • Lertkiatmongkol P, Liao D, Mei H, Hu Y, Newman PJ (2016) Endothelial functions of platelet/endothelial cell adhesion molecule-1 (CD31). Curr Opin Hematol 23:253–259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Masood R, Cai J, Zheng T, Smith DL, Hinton DR, Gill PS (2001) Vascular endothelial growth factor (VEGF) is an autocrine growth factor for VEGF receptor-positive human tumors. Blood 98:1904–1913

    Article  CAS  PubMed  Google Scholar 

  • Mathew M, Enzler T, Shu CA, Rizvi NA (2018) Combining chemotherapy with PD-1 blockade in NSCLC. Pharmacol Ther 186:130–137

    Article  CAS  PubMed  Google Scholar 

  • Mendonsa AM, Na TY, Gumbiner BM (2018) E-cadherin in contact inhibition and cancer. Oncogene 37:4769–4780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mohammad RM, Muqbil I, Lowe L, Yedjou C, Hsu HY, Lin LT, Siegelin MD, Fimognari C, Kumar NB, Dou QP et al (2015) Broad targeting of resistance to apoptosis in cancer. Semin Cancer Biol 35(Suppl):S78-s103

    Article  PubMed  PubMed Central  Google Scholar 

  • Nagase H, Visse R, Murphy G (2006) Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 69:562–573

    Article  CAS  PubMed  Google Scholar 

  • Rotow J, Bivona TG (2017) Understanding and targeting resistance mechanisms in NSCLC. Nat Rev Cancer 17:637–658

    Article  CAS  PubMed  Google Scholar 

  • Siegel RL, Miller KD, Jemal A (2020) Cancer statistics, 2020. CA Cancer J Clin 70:7–30

    Article  PubMed  Google Scholar 

  • Tait SW, Ichim G, Green DR (2014) Die another way–non-apoptotic mechanisms of cell death. J Cell Sci 127:2135–2144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tan DS, Yom SS, Tsao MS, Pass HI, Kelly K, Peled N, Yung RC, Wistuba II, Yatabe Y, Unger M et al (2016) The International Association for the Study of Lung Cancer consensus statement on optimizing management of EGFR mutation-positive non-small cell lung cancer: status in 2016. J Thorac Oncol 11:946–963

    Article  PubMed  Google Scholar 

  • Taylor RC, Cullen SP, Martin SJ (2008) Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol 9:231–241

    Article  CAS  PubMed  Google Scholar 

  • Thompson CB (1995) Apoptosis in the pathogenesis and treatment of disease. Science 267:1456–1462

    Article  CAS  PubMed  Google Scholar 

  • Tsesmetzis N, Paulin CBJ, Rudd SG, Herold N (2018) Nucleobase and nucleoside analogues: resistance and re-sensitisation at the level of pharmacokinetics, pharmacodynamics and metabolism. Cancers (Basel) 10:240

  • Wang Q, Liu X, Wang Q, Zhang Y, Jiang J, Guo X, Fan Q, Zheng L, Yu X, Wang N et al (2011) FNC, a novel nucleoside analogue inhibits cell proliferation and tumor growth in a variety of human cancer cells. Biochem Pharmacol 81:848–855

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Wang CP, Ding XX, Wang N, Ma F, Jiang JH, Wang QD, Chang JB (2014) FNC, a novel nucleoside analogue, blocks invasion of aggressive non-Hodgkin lymphoma cell lines via inhibition of the Wnt/β-catenin signaling pathway. Asian Pac J Cancer Prev 15:6829–6835

    Article  PubMed  Google Scholar 

  • Zhang Y, Zhang R, Ding X, Peng B, Wang N, Ma F, Peng Y, Wang Q, Chang J (2017) FNC efficiently inhibits mantle cell lymphoma growth. PLoS ONE 12:e0174112

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This study was supported by the Scientific Research Project of Henan Institute of Medical and Pharmaceutical Sciences (2020SP0109).

Author information

Author notes

  1. Xiang Jing, Shuai Niu and Yi Liang contributed equally to this work.

Authors and Affiliations

  1. School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China

    Xiang Jing, Shuai Niu, Yi Liang & Wanying Yue

  2. Henan Institute of Medical and Pharmaceutical Sciences, Henan Key Laboratory for Pharmacology of Liver Diseases, Zhengzhou University, Zhengzhou, China

    Huiping Chen, Ning Wang, Youmei Peng, Fang Ma, Qingduan Wang & Yan Zhang

  3. School of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, China

    Junbiao Chang

  4. Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Yi Zhang

Authors
  1. Xiang Jing
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shuai Niu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yi Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Huiping Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ning Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Youmei Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Fang Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wanying Yue
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Qingduan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Junbiao Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization and writing—review and editing: YZ and YZ. Funding acquisition: YZ. Formal analysis and writing—original draft: XJ, SN and YL. Visualization: YL. Investigation: XJ, SN, YL, HC, NW, YP, FM, WY. Supervision: JC, QW, YZ and YZ. All authors reviewed the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yi Zhang or Yan Zhang.

Ethics declarations

Conflict of interest

The authors declare no competing financial interests.

Ethical approval and consent to participate

Animal experiments were approved by the Animal Experimentation Ethics Committee of Zhengzhou University (Henan, China).

Consent for publication

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jing, X., Niu, S., Liang, Y. et al. FNC inhibits non-small cell lung cancer by activating the mitochondrial apoptosis pathway. Genes Genom 44, 123–131 (2022). https://doi.org/10.1007/s13258-021-01179-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13258-021-01179-9

Keywords

Search

Navigation