Skip to main content

Advertisement

SpringerLink
Log in

Cucurbitacin IIb Extracted from Hemsleya penxianensis Induces Cell Cycle Arrest and Apoptosis in Bladder Cancer Cells by Regulating Cell Cycle Checkpoints and Mitochondrial Apoptotic Pathway

  • Correspondence
  • Published:
Plant Foods for Human Nutrition Aims and scope Submit manuscript

Abstract

Cucurbitacin IIb (CuIIb) extracted from Hemsleya penxianensis has been demonstrated anticancer activity in many malignancies, however, its effect against bladder cancer cells and the molecular mechanism remains unclear. Accordingly, in the present study, we evaluated the effect and further the underlying mechanism of CuIIb on bladder cancer cells. Cell viability and clonogenicity were examined to evaluate growth suppressive effect of CuIIb, alongside mechanism exploration was conducted based on RNA sequencing (RNA-seq). The results showed that CuIIb exposure inhibited the growth of T24 and UM-UC-3 bladder cancer cells as indicated by its obvious suppression on cell viability and clonogenicity. Mechanistic studies by RNA-seq and quantifying analysis of RNA-seq data by TMNP indicated cell cycle modulated by cell cycle checkpoints and apoptosis mediated by PI3K/Akt pathway might account for the anticancer activity of CuIIb. Consistently, results of flow cytometry and AO/EB staining demonstrated that the growth-suppressive effect of CuIIb was mediated by cell cycle arrest in G2/M phase and robust induction of cell apoptosis, which was further confirmed by immunoblotting and mitochondrial membrane potential (ΔΨm) analysis. Collectively, the results presented herein indicated that CuIIb exhibited anticancer activity on bladder cancer which may be a potential candidate for improving bladder cancer outcomes.

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

Data Availability

Data will be made available on request.

Abbreviations

CuIIb:

Cucurbitacin IIb

ATM:

Ataxia telangiectasia mutated kinase

NMIBC:

Non-muscle-invasive bladder cancer

NCSs:

Normalized correlation scores

TURBT:

Transurethral resection of the bladder tumor

DEGs:

Differentially Expressed Genes

MIBC:

Muscle-invasive bladder cancer

GO:

Gene Ontology

RNA-Seq:

RNA-sequencing

KEGG:

KEGG Ortholog database

ATR:

Ataxia telangiectasia and Rad3-related kinase

TMNP:

Target prediction module of transcriptome-based multi-scale network pharmacological platform

References

  1. Bogen JP, Grzeschik J, Jakobsen J, Bahre A, Hock B, Kolmar H (2021) Treating bladder cancer: engineering of current and next generation antibody-, fusion protein-, mRNA-, cell- and viral-based therapeutics. Front Oncol 11:672262. https://doi.org/10.3389/fonc.2021.672262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Babjuk M, Burger M, Comperat EM et al (2019) European association of urology guidelines on non-muscle-invasive bladder cancer (TaT1 and carcinoma in situ) – 2019 update. Eur Urol 76:639–657. https://doi.org/10.1016/j.eururo.2019.08.016

    Article  CAS  PubMed  Google Scholar 

  3. Ousati Ashtiani Z, Abbasi S, Pourmand G, Ghafouri-Fard S (2022) Overexpression of long intergenic noncoding RNAs in bladder cancer: a new insight to cancer diagnosis. Pathol Res Pract 235:153961. https://doi.org/10.1016/j.prp.2022.153961

    Article  CAS  PubMed  Google Scholar 

  4. Babjuk M, Bohle A, Burger M et al (2017) EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: Update 2016. Eur Urol 71:447–461. https://doi.org/10.1016/j.eururo.2016.05.041

    Article  PubMed  Google Scholar 

  5. Dasari S, Tchounwou PB (2014) Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol 740:364–378. https://doi.org/10.1016/j.ejphar.2014.07.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wang SG, Guan XH, Zhong XH, Yang ZP, Huang WL, Jia BY, Cui T (2016) Simultaneous determination of cucurbitacin IIa and cucurbitacin IIb of Hemsleya amabilis by HPLC-MS/MS and their pharmacokinetic study in normal and indomethacin-induced rats. Biomed Chromatogr 30:1632–1640. https://doi.org/10.1002/bmc.3733

    Article  CAS  PubMed  Google Scholar 

  7. Liu M, Yan Q, Peng B, Cai Y, Zeng SS, Xu ZJ, Yan YL, Gong ZC (2021) Use of cucurbitacins for lung cancer research and therapy. Cancer Chemother Pharmacol 88:1–14. https://doi-org.libaccess.fdu.edu/https://doi.org/10.1007/s00280-021-04265-7

    Article  PubMed  Google Scholar 

  8. Wei J, Yan YL, Chen X, Qian L, Zeng SS, Li Z, Dai S, Gong ZC, Xu ZJ (2019) The roles of plant-derived triptolide on non-small cell lung cancer. Oncol Res 27:849–858. https://doi.org/10.3727/096504018X15447833065047

    Article  PubMed  PubMed Central  Google Scholar 

  9. Wang Y, Zhao GX, Xu LH, Liu KP, Pan H, He J, Cai JY, Ouyang DY, He XH (2014) Cucurbitacin IIb exhibits anti-inflammatory activity through modulating multiple cellular behaviors of mouse lymphocytes. PLoS ONE 9:e89751. https://doi.org/10.1371/journal.pone.0089751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Torres-Moreno H, Marcotullio MC, Velazquez C, Iann F, Robles-Zepeda RE (2020) Cucurbitacin IIb, a steroidal triterpene from Ibervillea sonorae induces antiproliferative and apoptotic effects on cervical and lung cancer cells. Steroids 157:108597. https://doi.org/10.1016/j.steroids.2020.108597

    Article  CAS  PubMed  Google Scholar 

  11. Ren S, Ouyang DY, Saltis M, Xu LH, Zha QB, Cai JY, He XH (2012) Anti-proliferative effect of 23,24-dihydrocucurbitacin F on human prostate cancer cells through induction of actin aggregation and cofilin-actin rod formation. Cancer Chemother Pharmacol 70:415–424. https://doi.org/10.1007/s00280-012-1921-z

    Article  CAS  PubMed  Google Scholar 

  12. Liang Y, Zhang TH, Ren L, Jing SY, Li ZL, Zuo P, Li TZ, Wang YJ, Zhang J, Wei ZY (2021) Cucurbitacin IIb induces apoptosis and cell cycle arrest through regulating EGFR/MAPK pathway. Environ Toxicol Pharmacol 81:103542. https://doi.org/10.1016/j.etap.2020.103542

    Article  CAS  PubMed  Google Scholar 

  13. Torres-Moreno H, Marcotullio MC, Velazquez C, Arenas-Luna VM, Hernandez-Gutierrez S, Robles-Zepeda RE (2020) Cucurbitacin IIb from Ibervillea sonorae induces apoptosis and cell cycle arrest via STAT3 inhibition. Anticancer Agents Med Chem 20:1188–1196. https://doi.org/10.2174/1871520620666200415101701

    Article  CAS  PubMed  Google Scholar 

  14. Isono M, Okubo K, Asano T, Sato A (2021) Inhibition of checkpoint kinase 1 potentiates anticancer activity of gemcitabine in bladder cancer cells. Sci Rep 11:10181. https://doi.org/10.1038/s41598-021-89684-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yarden RI, Metsuyanim S, Pickholtz I, Shabbeer S, Tellio H, Papa MZ (2012) BRCA1-dependent Chk1 phosphorylation triggers partial chromatin disassociation of phosphorylated Chk1 and facilitates S-phase cell cycle arrest. Int J Biochem Cell Biol 44:1761–1769. https://doi.org/10.1016/j.biocel.2012.06.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Jin Z, Tao S, Zhang C, Xu DM, Zhu ZH (2022) KIF20A promotes the development of fibrosarcoma via PI3K-Akt signaling pathway. Exp Cell Res 420:113322. https://doi.org/10.1016/j.yexcr.2022.113322

    Article  CAS  PubMed  Google Scholar 

  17. Chen SS, Deng CP, Zheng WY, Li SH, Liu YP, Zhang T, Zhang C, Fu YH, Miao H, Ren FZ, Ma XY (2021) Cannabidiol effectively promoted cell death in bladder cancer and the improved intravesical adhesion drugs delivery strategy could be better used for treatment. Pharmaceutics 13. https://doi.org/10.3390/pharmaceutics13091415

  18. Cuadrado M, Gutierrez-Martinez P, Swat A, Nebreda AR, Fernandez-Capetillo O (2009) p27Kip1 stabilization is essential for the maintenance of cell cycle arrest in response to DNA damage. Cancer Res 69:8726–8732. https://doi.org/10.1158/0008-5472.CAN-09-0729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chaudhary P, Sharma R, Sahu M, Vishwanatha JK, Awasthi S, Awasthi YC (2013) 4-Hydroxynonenal induces G2/M phase cell cycle arrest by activation of the ataxia telangiectasia mutated and Rad3-related protein (ATR)/checkpoint kinase 1 (Chk1) signaling pathway. J Biol Chem 288:20532–20546. https://doi.org/10.1074/jbc.M113.467662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This research was supported by the National Natural Science Foundation of Hebei province (H2022201051), the National Natural Science Foundation of China (No. 82274363), and the CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2021-I2M-1-071).

Author information

Author notes

  1. Nan Chen, Peng Li and Litao Liu contributed equally to this work as co-first authors.

Authors and Affiliations

  1. College of Pharmaceutical Sciences, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding, 071002, China

    Nan Chen, Jun Zhang, Zepeng Cao, Ziwen Chen & Xiaowei Huo

  2. College of Basic Sciences, Shanxi Agricultural University, Taigu, 030801, China

    Peng Li

  3. Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, China

    Xudong Xu & Guoxu Ma

  4. Department of General Surgery, Affiliated Hospital of Hebei University, Baoding, 071002, China

    Litao Liu

Authors
  1. Nan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Litao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zepeng Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ziwen Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xudong Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Guoxu Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xiaowei Huo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization was performed by Xiaowei Huo and Guoxu Ma. Investigation and administration were performed by Nan Chen, Peng Li, Jun Zhang, Zepeng Cao, Ziwen Chen. Data analysis was performed by Nan Chen, Peng Li, Litao Liu and Xudong Xu. Xiaowei Huo and Litao Liu wrote the original draft. Litao Liu and Guoxu Ma reviewed and edited the draft. All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Guoxu Ma or Xiaowei Huo.

Ethics declarations

Ethics Approval

Not applicable.

Consent to Participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Conflict of Interest

All authors declared no conflict of interest.

Additional information

Publisher’s Note

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

Electronic Supplementary Material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, N., Li, P., Liu, L. et al. Cucurbitacin IIb Extracted from Hemsleya penxianensis Induces Cell Cycle Arrest and Apoptosis in Bladder Cancer Cells by Regulating Cell Cycle Checkpoints and Mitochondrial Apoptotic Pathway. Plant Foods Hum Nutr 78, 483–492 (2023). https://doi.org/10.1007/s11130-023-01058-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11130-023-01058-6

Keywords

Search

Navigation