Skip to main content
Log in

HS-173, a selective PI3K inhibitor, induces cell death in head and neck squamous cell carcinoma cell lines

  • original article
  • Published:
Wiener klinische Wochenschrift Aims and scope Submit manuscript

Summary

Background

The selective PI3K (Phosphatidylinositol 3-kinase) inhibitor HS-173 has anticancer activity in non-small cell lung cancer and pancreatic cancer cells. Of all head and neck squamous cell carcinomas (HNSCC) 20% harbor specific mutations in the genome. The aim of this study was to investigate the effect of HS-173 on HNSCC cell lines.

Methods

The cell lines SCC25, CAL27 and FaDu were incubated with HS-173. Its antiproliferative effect was determined using the CCK‑8 cell proliferation assay. Combined incubation with cisplatin was performed and combination index analysis was conducted. To investigate its effect on radiotherapy, cells were irradiated with 2, 4, 6 and 8 Gy, respectively. Synergistic effects of radiation and HS-173 were measured by proliferation assays and clonogenic survival.

Results

The use of HS-173 induced significant reduction of cell proliferation across all cell lines. Most interestingly, it showed a synergistic effect with cisplatin treatment. Clonogenic survival revealed a radiosensitizing effect in CAL27 and FaDu cells. The HS-173 caused significant induction of apoptosis in SCC25 and FaDu cells.

Conclusion

The selective PI3K inhibitor HS-173 is a potent chemosensitizing and also radiosensitizing drug in treatment of HNSCC cell lines and could be an effective treatment in PI3K-mutated HNSCC.

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

Access this article

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

Instant access to the full article PDF.

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

Similar content being viewed by others

References

  1. Haddad RI, Shin DM. Recent advances in head and neck cancer. N Engl J Med. 2008;359:1143–54.

    Article  CAS  Google Scholar 

  2. Asati V, Mahapatra DK, Bharti SK. PI3K/AKT/mTor and Ras/Raf/MEK/ERK signaling pathways inhibitors as anticancer agents: structural and pharmacological perspectives. Eur J Med Chem. 2016;109(C):314–41. https://doi.org/10.1016/j.ejmech.2016.01.012.

    Article  CAS  PubMed  Google Scholar 

  3. Freudlsperger C, Burnett JR, Friedman JA, Kannabiran VR, Chen Z, Van Waes C. EGFR–PI3K–AKT–mTOR signaling in head and neck squamous cell carcinomas: attractive targets for molecular-oriented therapy. Expert Opin Ther Targets. 2011;15(1):63–74. https://doi.org/10.1517/14728222.2011.541440.

    Article  CAS  PubMed  Google Scholar 

  4. Vermorken JB, Mesia R, Riviera F, et al. Platinum-based chemotherapyplus cetuximab in head and neck cancer. N Engl J Med. 2008;359:1116–27.

    Article  CAS  Google Scholar 

  5. Bussink J, Kaanders JHAM, van der Kogel AJ. Microenvironmental transformations by VEGF- and EGF-receptor inhibition and potential implications for responsiveness to radiotherapy. Radiother Oncol. 2007;82(1):10–7. https://doi.org/10.1016/j.radonc.2006.10.022.

    Article  CAS  PubMed  Google Scholar 

  6. Perri F, Pacelli R, Scarpati VDG, et al. Radioresistance in head and neck squamous cell carcinoma: biological bases and therapeutic implications. Head Neck. 2015;37(5):763–70. https://doi.org/10.1002/hed.23837.

    Article  PubMed  Google Scholar 

  7. Seiwert TY, Zuo Z, Keck MK, et al. Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas. Clin Cancer Res. 2015;21(3):632–41. https://doi.org/10.1158/1078-0432.CCR-13-3310.

    Article  CAS  PubMed  Google Scholar 

  8. Lui VWY, Hedberg ML, Li H, et al. Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer Discov. 2013;3(7):761–9. https://doi.org/10.1158/2159-8290.CD-13-0103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Garlich JR, De P, Dey N, et al. A vascular targeted pan phosphoinositide 3‑Kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity. Cancer Res. 2008;68(1):206–15. https://doi.org/10.1158/0008-5472.CAN-07-0669.

    Article  CAS  PubMed  Google Scholar 

  10. Michmerhuizen NL, et al. Rationale for using irreversible EGFR-Growth Factor Inhibitors in combination with Phosphatidylinositol3-kinase Inhihitors for advanced head and neck squamous cell carinoma. Mol Pharmacol. 2019;95(5):528–36.

    Article  CAS  Google Scholar 

  11. Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, et al. The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012;483:603–7.

    Article  CAS  Google Scholar 

  12. Kotowski U, Heiduschka G, Seemann R, et al. Wirkung des Kaffeebestandteils Cafestol auf Kopf-Hals-Tumorzelllinien. Strahlenther Onkol. 2015;191(6):511–7. https://doi.org/10.1007/s00066-014-0807-x.

    Article  PubMed  Google Scholar 

  13. Franken NAP, Rodermond HM, Stap J, Haveman J, van Bree C. Clonogenic assay of cells in vitro. Nat Protoc. 2006;1(5):2315–9. https://doi.org/10.1038/nprot.2006.339.

    Article  CAS  PubMed  Google Scholar 

  14. Wicki A, Mandalà M, Massi D, et al. Acquired resistance to clinical cancer therapy: a twist in physiological signaling. Physiol Rev. 2016;96(3):805–29. https://doi.org/10.1152/physrev.00024.2015.

    Article  CAS  PubMed  Google Scholar 

  15. Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008;27(41):5497–510. https://doi.org/10.1038/onc.2008.245.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kean B, Kim S, Ahn Y. In vitro anticancer activity of PI3K alpha selective inhibitor BYL719 in head and neck cancer. Anticancer Res. 2015;35:175–82.

    Google Scholar 

  17. Yang J, Nie J, Ma X, Wei Y, Peng Y, Wei X. Targeting PI3K in cancer. Mechanisms and advances in clinical trials. Mol Cancer. 2019;28:26.

    Article  Google Scholar 

  18. Barrientos JC. Idelalisib for the treatment of indolent non-Hodgkin lymphoma: a review of its clinical potential. Onco Thargets Ther. 2016;9:2945–53. https://doi.org/10.2147/OTT.S102573.

    Article  CAS  Google Scholar 

  19. Almasan A, Smith M, Hill B, Madanat Y. Idelalisib therapy of indolent B‑cell malignancies: chronic lymphocytic leukemia and small lymphocytic or follicular lymphomas. Blood Lymphat Cancer. 2016;6:1–6.

    PubMed  PubMed Central  Google Scholar 

  20. Schötz U, Balzer V, Brandt F. Dual PI3K/mTOR-inhibitor NVP-BEZ235 enhances radiosensitivity in head and neck squamous cell carcinoma (HNSCC) cell lines due to suppressed double-strand break (DSB) repair by non-homologous end joining. Cancers. 2020;12(2):467.

    Article  Google Scholar 

  21. Soulières D, Faivre S, Mesia R, et al. Buparlisib and paclitaxel in patients with platinum-Pretreated recurrent or metastatic squamous cell carcinoma of the head and neck (BERIL-1): a Randomised, double-blind, placebo-controlled phase 2 trial. Lancet Oncol. 2017;18(3):323–35.

    Article  Google Scholar 

  22. Kim SJ, Jung KH, Son MK, et al. Tumor vessel normalization by the PI3K-inhibitor HS-173 enhances drug delivery. Cancer Lett. 2017;403:339–53.

    Article  CAS  Google Scholar 

  23. Stausbol-Gron B, Overgaard J. Relationship between tumour cell in vitro radiosensitivity and clinical outcome after curative radiotherapy for squamous cell carcinoma of the head and neck. Radiother Oncol. 1999;50:47–55.

    Article  CAS  Google Scholar 

  24. Baker SJ. PTEN enters the nuclear age. Cell. 2007;128(1):25–8. https://doi.org/10.1016/j.cell.2006.12.02.

    Article  CAS  PubMed  Google Scholar 

  25. Park JH, Jung KH, Kim SH, et al. Radiosensitization of the PI3K-Inhibitor of HS-173 through reduction of DNA damage repair in pancreatic cancer. Oncotarget. 2017;8(68):112893–906.

    Article  Google Scholar 

  26. Michmerhuizen NL, Leonard E, Kulkarni A, Brenner JD. Differential compensation mechanisms define resistance to PI3K inhibitors in PIK3CA amplified HNSCC. Otorhinolaryngol Head Neck Surg. 2016;1(2):44–50.

    Article  Google Scholar 

  27. Niehr F, Eder T, Pilz T, et al. Multilayered omics-based analysis of a head and neck cancer model of cisplatin resistance reveals intratumoral heterogeneity and treatment-induced clonal selection. Clin Cancer Res. 2018;14(1):158–68.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gregor Heiduschka MD, PD.

Ethics declarations

Conflict of interest

E. Foki, I. Stanisz, L. Kadletz, U. Kotowski, R. Seemann, R. Schmid, and G. Heiduschka declare that they have no competing interests.

Ethical standards

This study has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

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

Foki, E., Stanisz, I., Kadletz, L. et al. HS-173, a selective PI3K inhibitor, induces cell death in head and neck squamous cell carcinoma cell lines. Wien Klin Wochenschr 133, 26–31 (2021). https://doi.org/10.1007/s00508-020-01729-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00508-020-01729-3

Keywords

Navigation