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Erschienen in: Clinical and Translational Oncology 8/2019

10.01.2019 | Research Article

A comparative assessment of the effects of integrin inhibitor cilengitide on primary culture of head and neck squamous cell carcinoma (HNSCC) and HNSCC cell lines

verfasst von: L. Zhang, A. Gülses, N. Purcz, J. Weimer, J. Wiltfang, Y. Açil

Erschienen in: Clinical and Translational Oncology | Ausgabe 8/2019

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Abstract

Background

Integrins are highly attractive targets in oncology due to their involvement in angiogenesis in a wide spectrum of cancer entities. Among several integrin inhibitors, cilengitide is suggested to be one of the most promising inhibitors. However, little is known about the cellular processes induced during cilengitide chemotherapy in head and neck squamous cell carcinoma (HNSCC).

Materials and methods

For the current study, 3 HNSCC cell lines, SCC4, SCC15 and SCC25; and 3 primary culture cells, TU53, TU57, and TU63 were used. CD90, cytokeratin, and vimentin were stained immunohistochemically to identify the biological characteristics of these cell lines and primary culture cells and the cytostatic effect of cilengitide was evaluated. Quantitative polymerase chain reaction (qPCR) arrays were applied to evaluate target protein genes ITGAV, ITGB3, and ITGB5 of integrin αvβ3 and αvβ5 at respective concentrations of 50 and 100 μM cilengitide for 72 h.

Results

Cilengitide has significantly inhibited the proliferation of HNSCC cells in a dose-dependent way. At the same concentration, cilengitide suppressed the proliferation of primary culture cells even more strongly than it did that of cell lines, suggesting that primary culture cells retain more of their internal biological characteristics than do cell lines. qPCR assay detected downregulation of ITGAV, ITGB3, and ITGB5 gene expression after exposure to 50 μM of cilengitide. However, after exposure to 100-μM cilengitide, expression of these genes significantly increased both in cell lines and primary culture cells.

Conclusions

RGD-containing small-molecule synthetic peptides might be considered in tumor chemotherapy in the near future. The different reactions of primary culture cells and cell lines demonstrated that individualized chemotherapy plans may be a feasible option. However, research on the role of cilengitide in HNSCC therapy is still in its early stages, and further investigations are required.
Literatur
1.
Zurück zum Zitat Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRef Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRef
2.
Zurück zum Zitat de Bree R, Deurloo EE, Snow GB, Leemans CR. Screening for distant metastases in patients with head and neck cancer. Laryngoscope. 2000;110:397–401.CrossRefPubMed de Bree R, Deurloo EE, Snow GB, Leemans CR. Screening for distant metastases in patients with head and neck cancer. Laryngoscope. 2000;110:397–401.CrossRefPubMed
3.
Zurück zum Zitat Denaro N, Russi EG, Colantonio I, Adamo V, Merlano MC. The role of antiangiogenic agents in the treatment of head and neck cancer. Oncology. 2012;83:108–16.CrossRefPubMed Denaro N, Russi EG, Colantonio I, Adamo V, Merlano MC. The role of antiangiogenic agents in the treatment of head and neck cancer. Oncology. 2012;83:108–16.CrossRefPubMed
4.
Zurück zum Zitat Liotta LA, Stetler-Stevenson WG. Tumor invasion and metastasis: an imbalance of positive and negative regulation. Can Res. 1991;51:5054s–9s. Liotta LA, Stetler-Stevenson WG. Tumor invasion and metastasis: an imbalance of positive and negative regulation. Can Res. 1991;51:5054s–9s.
6.
Zurück zum Zitat Lester BR, McCarthy JB. Tumor cell adhesion to the extracellular matrix and signal transduction mechanisms implicated in tumor cell motility, invasion and metastasis. Cancer Metastasis Rev. 1992;11:31–44.CrossRefPubMed Lester BR, McCarthy JB. Tumor cell adhesion to the extracellular matrix and signal transduction mechanisms implicated in tumor cell motility, invasion and metastasis. Cancer Metastasis Rev. 1992;11:31–44.CrossRefPubMed
7.
Zurück zum Zitat Raguse JD, Gath HJ, Bier J, Riess H, Oettle H. Cilengitide (EMD 121974) arrests the growth of a heavily pretreated highly vascularised head and neck tumour. Oral Oncol. 2004;40:228–30.CrossRefPubMed Raguse JD, Gath HJ, Bier J, Riess H, Oettle H. Cilengitide (EMD 121974) arrests the growth of a heavily pretreated highly vascularised head and neck tumour. Oral Oncol. 2004;40:228–30.CrossRefPubMed
8.
Zurück zum Zitat Kumagai H, Tajima M, Ueno Y, Giga-Hama Y, Ohba M. Effect of cyclic RGD peptide on cell adhesion and tumor metastasis. Biochem Biophys Res Commun. 1991;177:74–82.CrossRefPubMed Kumagai H, Tajima M, Ueno Y, Giga-Hama Y, Ohba M. Effect of cyclic RGD peptide on cell adhesion and tumor metastasis. Biochem Biophys Res Commun. 1991;177:74–82.CrossRefPubMed
9.
Zurück zum Zitat Scaringi C, Minniti G, Caporello P, Enrici RM. Integrin inhibitor cilengitide for the treatment of glioblastoma: a brief overview of current clinical results. Anticancer Res. 2012;32:4213–23.PubMed Scaringi C, Minniti G, Caporello P, Enrici RM. Integrin inhibitor cilengitide for the treatment of glioblastoma: a brief overview of current clinical results. Anticancer Res. 2012;32:4213–23.PubMed
10.
Zurück zum Zitat Reardon DA, Neyns B, Weller M, Tonn JC, Nabors LB, Stupp R. Cilengitide: an RGD pentapeptide alphanubeta3 and alphanubeta5 integrin inhibitor in development for glioblastoma and other malignancies. Future Oncol. 2011;7:339–54.CrossRefPubMed Reardon DA, Neyns B, Weller M, Tonn JC, Nabors LB, Stupp R. Cilengitide: an RGD pentapeptide alphanubeta3 and alphanubeta5 integrin inhibitor in development for glioblastoma and other malignancies. Future Oncol. 2011;7:339–54.CrossRefPubMed
11.
Zurück zum Zitat Heiduschka G, Lill C, Schneider S, et al. The effect of cilengitide in combination with irradiation and chemotherapy in head and neck squamous cell carcinoma cell lines. Strahlenther Onkol Organ Dtsch Rontgenges. 2014;190:472–9.CrossRef Heiduschka G, Lill C, Schneider S, et al. The effect of cilengitide in combination with irradiation and chemotherapy in head and neck squamous cell carcinoma cell lines. Strahlenther Onkol Organ Dtsch Rontgenges. 2014;190:472–9.CrossRef
12.
Zurück zum Zitat Vermorken JB, Peyrade F, Krauss J, et al. Cisplatin, 5-fluorouracil, and cetuximab (PFE) with or without cilengitide in recurrent/metastatic squamous cell carcinoma of the head and neck: results of the randomized phase I/II ADVANTAGE trial (phase II part). Ann Oncol. 2014;25:682–8.CrossRefPubMedPubMedCentral Vermorken JB, Peyrade F, Krauss J, et al. Cisplatin, 5-fluorouracil, and cetuximab (PFE) with or without cilengitide in recurrent/metastatic squamous cell carcinoma of the head and neck: results of the randomized phase I/II ADVANTAGE trial (phase II part). Ann Oncol. 2014;25:682–8.CrossRefPubMedPubMedCentral
13.
Zurück zum Zitat Cedra S, Wiegand S, Kolb M, Dietz A, Wichmann G. Reduced cytokine release in ex vivo response to cilengitide and cetuximab is a marker for improved survival of head and neck cancer patients. Cancers. 2017;9:117.CrossRefPubMedCentral Cedra S, Wiegand S, Kolb M, Dietz A, Wichmann G. Reduced cytokine release in ex vivo response to cilengitide and cetuximab is a marker for improved survival of head and neck cancer patients. Cancers. 2017;9:117.CrossRefPubMedCentral
14.
Zurück zum Zitat Li Y, Cui JT. Inhibition of Bcl-2 potentiates AZD-2014-induced anti-head and neck squamous cell carcinoma cell activity. Biochem Biophys Res Commun. 2016;477:607–13.CrossRefPubMed Li Y, Cui JT. Inhibition of Bcl-2 potentiates AZD-2014-induced anti-head and neck squamous cell carcinoma cell activity. Biochem Biophys Res Commun. 2016;477:607–13.CrossRefPubMed
15.
Zurück zum Zitat Manikandan M, Deva Magendhra Rao AK, Arunkumar G, et al. Oral squamous cell carcinoma: microRNA expression profiling and integrative analyses for elucidation of tumourigenesis mechanism. Mol Cancer. 2016;15:28.CrossRefPubMedPubMedCentral Manikandan M, Deva Magendhra Rao AK, Arunkumar G, et al. Oral squamous cell carcinoma: microRNA expression profiling and integrative analyses for elucidation of tumourigenesis mechanism. Mol Cancer. 2016;15:28.CrossRefPubMedPubMedCentral
16.
Zurück zum Zitat Jovanovic J, Takagi J, Choulier L, et al. alphaVbeta6 is a novel receptor for human fibrillin-1: comparative studies of molecular determinants underlying integrin-rgd affinity and specificity. J Biol Chem. 2007;282:6743–51.CrossRefPubMed Jovanovic J, Takagi J, Choulier L, et al. alphaVbeta6 is a novel receptor for human fibrillin-1: comparative studies of molecular determinants underlying integrin-rgd affinity and specificity. J Biol Chem. 2007;282:6743–51.CrossRefPubMed
17.
Zurück zum Zitat Ten Hagen TL, Seynhaeve AL, de Wiel-Ambagtsheer G, et al. The alphaVbeta3/alphaVbeta5 integrin inhibitor cilengitide augments tumor response to melphalan isolated limb perfusion in a sarcoma model. Int J Cancer. 2013;132:2694–704.CrossRefPubMed Ten Hagen TL, Seynhaeve AL, de Wiel-Ambagtsheer G, et al. The alphaVbeta3/alphaVbeta5 integrin inhibitor cilengitide augments tumor response to melphalan isolated limb perfusion in a sarcoma model. Int J Cancer. 2013;132:2694–704.CrossRefPubMed
18.
Zurück zum Zitat Nabors LB, Mikkelsen T, Rosenfeld SS, et al. Phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma. J Clin Oncol. 2007;25:1651–7.CrossRefPubMed Nabors LB, Mikkelsen T, Rosenfeld SS, et al. Phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma. J Clin Oncol. 2007;25:1651–7.CrossRefPubMed
19.
Zurück zum Zitat Gerstner ER, Ye X, Duda DG, et al. A phase I study of cediranib in combination with cilengitide in patients with recurrent glioblastoma. Neuro-oncology. 2015;17:1386–92.CrossRefPubMedPubMedCentral Gerstner ER, Ye X, Duda DG, et al. A phase I study of cediranib in combination with cilengitide in patients with recurrent glioblastoma. Neuro-oncology. 2015;17:1386–92.CrossRefPubMedPubMedCentral
20.
Zurück zum Zitat Vansteenkiste J, Barlesi F, Waller CF, et al. Cilengitide combined with cetuximab and platinum-based chemotherapy as first-line treatment in advanced non-small-cell lung cancer (NSCLC) patients: results of an open-label, randomized, controlled phase II study (CERTO). Ann Oncol. 2015;26:1734–40.CrossRefPubMed Vansteenkiste J, Barlesi F, Waller CF, et al. Cilengitide combined with cetuximab and platinum-based chemotherapy as first-line treatment in advanced non-small-cell lung cancer (NSCLC) patients: results of an open-label, randomized, controlled phase II study (CERTO). Ann Oncol. 2015;26:1734–40.CrossRefPubMed
21.
Zurück zum Zitat Arul M, Roslani AC, Cheah SH. Heterogeneity in cancer cells: variation in drug response in different primary and secondary colorectal cancer cell lines in vitro. In Vitro Cell Dev Biol Anim. 2017;53(5):435–47.CrossRefPubMed Arul M, Roslani AC, Cheah SH. Heterogeneity in cancer cells: variation in drug response in different primary and secondary colorectal cancer cell lines in vitro. In Vitro Cell Dev Biol Anim. 2017;53(5):435–47.CrossRefPubMed
22.
Zurück zum Zitat Nabors LB, Mikkelsen T, Rosenfeld SS, et al. Phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma. J Clin Oncol. 2007;25(13):1651–7.CrossRefPubMed Nabors LB, Mikkelsen T, Rosenfeld SS, et al. Phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma. J Clin Oncol. 2007;25(13):1651–7.CrossRefPubMed
23.
24.
Zurück zum Zitat Eisele G, Wick A, Eisele AC, et al. Cilengitide treatment of newly diagnosed glioblastoma patients does not alter patterns of progression. J Neurooncol. 2014;117:141–5.CrossRefPubMed Eisele G, Wick A, Eisele AC, et al. Cilengitide treatment of newly diagnosed glioblastoma patients does not alter patterns of progression. J Neurooncol. 2014;117:141–5.CrossRefPubMed
25.
Zurück zum Zitat Reynolds AR, Hart IR, Watson AR, et al. Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors. Nat Med. 2009;15:392–400.CrossRefPubMed Reynolds AR, Hart IR, Watson AR, et al. Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors. Nat Med. 2009;15:392–400.CrossRefPubMed
26.
Zurück zum Zitat Fabricius EM, Wildner GP, Kruse-Boitschenko U, Hoffmeister B, Goodman SL, Raguse JD. Immunohistochemical analysis of integrins alphavbeta3, alphavbeta5 and alpha5beta1, and their ligands, fibrinogen, fibronectin, osteopontin and vitronectin, in frozen sections of human oral head and neck squamous cell carcinomas. Exp Ther Med. 2011;2:9–19.CrossRefPubMed Fabricius EM, Wildner GP, Kruse-Boitschenko U, Hoffmeister B, Goodman SL, Raguse JD. Immunohistochemical analysis of integrins alphavbeta3, alphavbeta5 and alpha5beta1, and their ligands, fibrinogen, fibronectin, osteopontin and vitronectin, in frozen sections of human oral head and neck squamous cell carcinomas. Exp Ther Med. 2011;2:9–19.CrossRefPubMed
27.
Zurück zum Zitat Vermorken JB, Guigay J, Mesia R, et al. Phase I/II trial of cilengitide with cetuximab, cisplatin and 5-fluorouracil in recurrent and/or metastatic squamous cell cancer of the head and neck: findings of the phase I part. Br J Cancer. 2011;104:1691–6.CrossRefPubMedPubMedCentral Vermorken JB, Guigay J, Mesia R, et al. Phase I/II trial of cilengitide with cetuximab, cisplatin and 5-fluorouracil in recurrent and/or metastatic squamous cell cancer of the head and neck: findings of the phase I part. Br J Cancer. 2011;104:1691–6.CrossRefPubMedPubMedCentral
Metadaten
Titel
A comparative assessment of the effects of integrin inhibitor cilengitide on primary culture of head and neck squamous cell carcinoma (HNSCC) and HNSCC cell lines
verfasst von
L. Zhang
A. Gülses
N. Purcz
J. Weimer
J. Wiltfang
Y. Açil
Publikationsdatum
10.01.2019
Verlag
Springer International Publishing
Erschienen in
Clinical and Translational Oncology / Ausgabe 8/2019
Print ISSN: 1699-048X
Elektronische ISSN: 1699-3055
DOI
https://doi.org/10.1007/s12094-018-02025-3

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