In vitro effects of gamma-secretase inhibition in HPV-positive and HPV-negative head and neck squamous cell carcinoma.
Gamma-secretase inhibitor
Head and neck squamous cell carcinoma
Notch pathway
Journal
Investigational new drugs
ISSN: 1573-0646
Titre abrégé: Invest New Drugs
Pays: United States
ID NLM: 8309330
Informations de publication
Date de publication:
04 2023
04 2023
Historique:
received:
02
01
2023
accepted:
25
01
2023
medline:
1
5
2023
pubmed:
23
2
2023
entrez:
22
2
2023
Statut:
ppublish
Résumé
New chemotherapy agents are warranted for head and neck squamous cell carcinoma (HNSCC), particularly for incidence-rising HPV-positive tumors. Based on the evidence of Notch pathway involvement in cancer promotion and progression, we aimed to gain insights into the in vitro antineoplastic effects of gamma-secretase inhibition in HPV-positive and -negative HNSCC models. All in vitro experiments were conducted in two HPV-negative (Cal27 and FaDu) and one HPV-associated HNSCC cell line (SCC154). The influence of the gamma-secretase inhibitor PF03084014 (PF) on proliferation, migration, colony forming, and apoptosis was assessed. We observed significant anti-proliferative, anti-migratory, anti-clonogenic, and pro-apoptotic effects in all three HNSCC cell lines. Furthermore, synergistic effects with concomitant radiation were observable in the proliferation assay. Interestingly, effects were slightly more potent in the HPV-positive cells. We provided novel insights into the potential therapeutic relevance of gamma-secretase inhibition in HNSCC cell lines in vitro. Therefore, PF may become a viable treatment option for patients with HNSCC, particularly for patients with HPV-induced malignancy. Indeed, further in vitro and in vivo experiments should be conducted to validate our results and decipher the mechanism behind the observed anti-neoplastic effects.
Sections du résumé
BACKGROUND
New chemotherapy agents are warranted for head and neck squamous cell carcinoma (HNSCC), particularly for incidence-rising HPV-positive tumors. Based on the evidence of Notch pathway involvement in cancer promotion and progression, we aimed to gain insights into the in vitro antineoplastic effects of gamma-secretase inhibition in HPV-positive and -negative HNSCC models.
METHODS
All in vitro experiments were conducted in two HPV-negative (Cal27 and FaDu) and one HPV-associated HNSCC cell line (SCC154). The influence of the gamma-secretase inhibitor PF03084014 (PF) on proliferation, migration, colony forming, and apoptosis was assessed.
RESULTS
We observed significant anti-proliferative, anti-migratory, anti-clonogenic, and pro-apoptotic effects in all three HNSCC cell lines. Furthermore, synergistic effects with concomitant radiation were observable in the proliferation assay. Interestingly, effects were slightly more potent in the HPV-positive cells.
CONCLUSION
We provided novel insights into the potential therapeutic relevance of gamma-secretase inhibition in HNSCC cell lines in vitro. Therefore, PF may become a viable treatment option for patients with HNSCC, particularly for patients with HPV-induced malignancy. Indeed, further in vitro and in vivo experiments should be conducted to validate our results and decipher the mechanism behind the observed anti-neoplastic effects.
Identifiants
pubmed: 36809443
doi: 10.1007/s10637-023-01334-x
pii: 10.1007/s10637-023-01334-x
pmc: PMC10140088
doi:
Substances chimiques
Amyloid Precursor Protein Secretases
EC 3.4.-
Antineoplastic Agents
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
193-201Informations de copyright
© 2023. The Author(s).
Références
Sturgis EM, Cinciripini PM (2007) Trends in head and neck cancer incidence in relation to smoking prevalence: an emerging epidemic of human papillomavirus-associated cancers? Cancer 110(7):1429–1435. https://doi.org/10.1002/cncr.22963
doi: 10.1002/cncr.22963
pubmed: 17724670
Chow LQM (2020) Head and neck cancer. N Engl J Med 382(1):60–72. https://doi.org/10.1056/NEJMra1715715
doi: 10.1056/NEJMra1715715
pubmed: 31893516
Alp AG (2012) İnsan Papillomavirusunun Genomik Yapısı ve Proteinleri [Genomic organization and proteins of human papillomavirus]. Mikrobiyol Bul 46(3):507–515
Powell SF, Lexi V, Spanos WC, Pyeon D (2021) The key differences between hjuman papillomavirus-positive and -negative head and neck cancers: biological and clinical implications. Cancers (Basel) 13(20):5206. https://doi.org/10.3390/cancers13205206
doi: 10.3390/cancers13205206
pubmed: 34680354
Licitra L, Perrone F, Bossi P, Suardi S, Mariani L, Artusi R, Oggionni M, Rossini C, Cantù G, Squadrelli M, Quattrone P, Locati LD, Bergamini C, Olmi P, Pierotti MA, Pilotti S (2006) High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol 24(36):5630–5636. https://doi.org/10.1200/JCO.2005.04.6136
doi: 10.1200/JCO.2005.04.6136
pubmed: 17179101
Posner MR, Lorch JH, Goloubeva O, Tan M, Schumaker LM, Sarlis NJ, Haddad RI, Cullen KJ (2011) Survival and human papillomavirus in oropharynx cancer in TAX 324: a subset analysis from an international phase III trial. Ann Oncol 22(5):1071–1077. https://doi.org/10.1093/annonc/mdr006
doi: 10.1093/annonc/mdr006
pubmed: 21317223
pmcid: 4351352
Fakhry C, Westra WH, Li S, Cmelak A, Ridge JA, Pinto H, Forastiere A, Gillison ML (2008) Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 100(4):261–9. https://doi.org/10.1093/jnci/djn011
doi: 10.1093/jnci/djn011
pubmed: 18270337
Seiwert TY, Zuo Z, Keck MK, Khattri A, Pedamallu CS, Stricker T, Brown C, Pugh TJ, Stojanov P, Cho J, Lawrence MS, Getz G, Brägelmann J, DeBoer R, Weichselbaum RR, Langerman A, Portugal L, Blair E, Stenson K, Lingen MW, Cohen EE, Vokes EE, White KP, Hammerman PS (2015) Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas. Clin Cancer Res 21(3):632–641. https://doi.org/10.1158/1078-0432.CCR-13-3310
doi: 10.1158/1078-0432.CCR-13-3310
pubmed: 25056374
Gillison ML, D’Souza G, Westra W, Sugar E, Xiao W, Begum S, Viscidi R (2008) Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst 100(6):407–420. https://doi.org/10.1093/jnci/djn025
doi: 10.1093/jnci/djn025
pubmed: 18334711
Yu W, Chen Y, Putluri N, Coarfa C, Robertson MJ, Putluri V, Stossi F, Dubrulle J, Mancini MA, Pang JC, Nguyen T, Baluya D, Myers JN, Lai SY, Sandulache VC (2020) Acquisition of cisplatin resistance shifts head and neck squamous cell carcinoma metabolism toward neutralization of oxidative stress. Cancers (Basel) 12(6):1670. https://doi.org/10.3390/cancers12061670
doi: 10.3390/cancers12061670
pubmed: 32599707
Hohnloser JH, Schierl R, Hasford B, Emmerich B (1996) Cisplatin based chemotherapy in testicular cancer patients: long term platinum excretion and clinical effects. Eur J Med Res 1(11):509–514
pubmed: 9438151
Astolfi L, Ghiselli S, Guaran V, Chicca M, Simoni E, Olivetto E, Lelli G, Martini A (2013) Correlation of adverse effects of cisplatin administration in patients affected by solid tumors: a retrospective evaluation. Oncol Rep 29(4):1285–1292. https://doi.org/10.3892/or.2013.2279
doi: 10.3892/or.2013.2279
pubmed: 23404427
pmcid: 3621656
Marur S, Forastiere AA (2016) Head and neck squamous cell carcinoma: update on epidemiology, diagnosis, and treatment. Mayo Clin Proc 91(3):386–396. https://doi.org/10.1016/j.mayocp.2015.12.017
doi: 10.1016/j.mayocp.2015.12.017
pubmed: 26944243
McCaw TR, Inga E, Chen H, Jaskula-Sztul R, Dudeja V, Bibb JA, Ren B, Rose JB (2021) Gamma secretase inhibitors in cancer: a current perspective on clinical performance. Oncologist 26(4):e608–e621. https://doi.org/10.1002/onco.13627
doi: 10.1002/onco.13627
pubmed: 33284507
pmcid: 8018325
Li L, Tang P, Li S, Qin X, Yang H, Wu C, Liu Y (2017) Notch signaling pathway networks in cancer metastasis: a new target for cancer therapy. Med Oncol 34(10):180. https://doi.org/10.1007/s12032-017-1039-6
doi: 10.1007/s12032-017-1039-6
pubmed: 28918490
Leethanakul C, Patel V, Gillespie J, Pallente M, Ensley JF, Koontongkaew S, Liotta LA, Emmert-Buck M, Gutkind JS (2000) Distinct pattern of expression of differentiation and growth-related genes in squamous cell carcinomas of the head and neck revealed by the use of laser capture microdissection and cDNA arrays. Oncogene 19(28):3220–3224. https://doi.org/10.1038/sj.onc.1203703
doi: 10.1038/sj.onc.1203703
pubmed: 10918578
Fukusumi T, Califano JA (2018) The NOTCH pathway in head and neck squamous cell carcinoma. J Dent Res 97(6):645–653. https://doi.org/10.1177/0022034518760297
doi: 10.1177/0022034518760297
pubmed: 29489439
pmcid: 5960881
Olsauskas-Kuprys R, Zlobin A, Osipo C (2013) Gamma secretase inhibitors of Notch signaling. Onco Targets Ther 23(6):943–955. https://doi.org/10.2147/OTT.S33766
doi: 10.2147/OTT.S33766
ATCC.org, “UPCI:SCC154; FaDu; Cal27,” ATCC, [Online]. Available: https://www.atcc.org/products/crl-3241#:~:text=The%20UPCI%3ASCC154%20cell%20line,squamous%20cell%20carcinoma%20(OPSCC . Accessed 20 Oct 2022
selleckchem.com, “Nirogacestat (PF03084014),” Selleckchem.com, [Online]. Available: https://www.selleckchem.com/products/pf-03084014-pf-3084014.html . Accessed 20 Oct 2022
Perri F, Longo F, Caponigro F, Sandomenico F, Guida A, Della Vittoria Scarpati G, Ottaiano A, Muto P, Ionna F (2020) Management of HPV-related squamous cell carcinoma of the head and neck: pitfalls and caveat. Cancers (Basel) 12(4):975. https://doi.org/10.3390/cancers12040975
doi: 10.3390/cancers12040975
pubmed: 32326465
Brkic FF, Kadletz-Wanke L, Kenner L, Füreder T, Jank B, Brunner M, Heiduschka G (2021) An analysis of distant metastasis cases from HPV-associated oropharyngeal squamous cell carcinoma. J Craniomaxillofac Surg 49(4):312–316. https://doi.org/10.1016/j.jcms.2021.01.012
doi: 10.1016/j.jcms.2021.01.012
pubmed: 33612410
Brkic FF, Mayer C, Besser G, Altorjai G, Herrmann H, Heiduschka G, Haymerle G, Kadletz-Wanke L (2021) Potential association of the prognostic index and survival in patients with p16-positive oropharyngeal squamous cell carcinoma. Wien Klin Wochenschr 133(21–22):1117–1121. https://doi.org/10.1007/s00508-021-01885-0
doi: 10.1007/s00508-021-01885-0
pubmed: 34143263
pmcid: 8599407
Porceddu SV, Daniels C, Yom SS, Liu H, Waldron J, Gregoire V, Moore A, Veness M, Yao M, Johansen J, Mehanna H, Rischin D, Le QT (2020) Head and Neck Cancer International Group (HNCIG) consensus guidelines for the delivery of postoperative radiation therapy in complex Cutaneous Squamous Cell Carcinoma of the Head and Neck (cSCCHN). Int J Radiat Oncol Biol Phys 107(4):641–651. https://doi.org/10.1016/j.ijrobp.2020.03.024
doi: 10.1016/j.ijrobp.2020.03.024
pubmed: 32289475
Liu C, Mann D, Sinha UK, Kokot NC (2018) The molecular mechanisms of increased radiosensitivity of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC): an extensive review. J Otolaryngol Head Neck Surg 47(1):59. https://doi.org/10.1186/s40463-018-0302-y
doi: 10.1186/s40463-018-0302-y
pubmed: 30241572
pmcid: 6150985
Özcan-Wahlbrink M, Schifflers C, Riemer AB (2019) Enhanced radiation sensitivity of human papillomavirus-driven head and neck cancer: focus on immunological aspects. Front Immunol 3(10):2831. https://doi.org/10.3389/fimmu.2019.02831
doi: 10.3389/fimmu.2019.02831
Bamps M, Dok R, Nuyts S (2021) The DNA damage response is differentially involved in HPV-positive and HPV-negative radioresistant head and neck squamous cell carcinoma. Cancers (Basel) 13(15):3717. https://doi.org/10.3390/cancers13153717
doi: 10.3390/cancers13153717
pubmed: 34359617
Brkic FF, Stoiber S, Maier T, Gurnhofer E, Kenner L, Heiduschka G, Kadletz-Wanke L (2022) Targeting Wnt/Beta-Catenin signaling in HPV-positive head and neck squamous cell carcinoma. Pharmaceuticals (Basel) 15(3):378. https://doi.org/10.3390/ph15030378
doi: 10.3390/ph15030378
pubmed: 35337176
Lan G, Lin Z, Zhang J, Liu L, Zhang J, Zheng L, Luo Q (2019) Notch pathway is involved in the suppression of colorectal cancer by embryonic stem cell microenvironment. Onco Targets Ther 16(12):2869–2878. https://doi.org/10.2147/OTT.S199046
doi: 10.2147/OTT.S199046
Farah E, Li C, Cheng L, Kong Y, Lanman NA, Pascuzzi P, Lorenz GR, Zhang Y, Ahmad N, Li L, Ratliff T, Liu X (2019) NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells. J Biol Chem 294(21):8543–8554. https://doi.org/10.1074/jbc.RA118.006983
doi: 10.1074/jbc.RA118.006983
pubmed: 30940724
pmcid: 6544854
Yuan CH, Filippova M, Duerksen-Hughes P (2012) Modulation of apoptotic pathways by human papillomaviruses (HPV): mechanisms and implications for therapy. Viruses 4(12):3831–3850. https://doi.org/10.3390/v4123831
doi: 10.3390/v4123831
pubmed: 23250450
pmcid: 3528293
Ye QF, Zhang YC, Peng XQ, Long Z, Ming YZ, He LY (2012) Silencing Notch-1 induces apoptosis and increases the chemosensitivity of prostate cancer cells to docetaxel through Bcl-2 and Bax. Oncol Lett 3(4):879–884. https://doi.org/10.3892/ol.2012.572
doi: 10.3892/ol.2012.572
pubmed: 22741011
pmcid: 3362393
Dai MY, Fang F, Zou Y, Yi X, Ding YJ, Chen C, Tao ZZ, Chen SM (2015) Downregulation of Notch1 induces apoptosis and inhibits cell proliferation and metastasis in laryngeal squamous cell carcinoma. Oncol Rep 34(6):3111–3119. https://doi.org/10.3892/or.2015.4274
doi: 10.3892/or.2015.4274
pubmed: 26398771