Oncotarget

Research Papers:

A combination of a ribonucleotide reductase inhibitor and histone deacetylase inhibitors downregulates EGFR and triggers BIM-dependent apoptosis in head and neck cancer

Roland H. Stauber, Shirley K. Knauer, Negusse Habtemichael, Carolin Bier, Britta Unruhe, Simona Weisheit, Stephanie Spange, Frank Nonnenmacher, Verena Fetz, Torsten Ginter, Sigrid Reichardt, Claus Liebmann, Günter Schneider and Oliver H. Krämer _

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Oncotarget. 2012; 3:31-43. https://doi.org/10.18632/oncotarget.430

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Abstract

Roland H. Stauber1,*, Shirley K. Knauer2,*, Negusse Habtemichael1, Carolin Bier1, Britta Unruhe2, Simona Weisheit3, Stephanie Spange3, Frank Nonnenmacher4, Verena Fetz1, Torsten Ginter3, Sigrid Reichardt3,  Claus Liebmann3, Günter Schneider5, Oliver H. Krämer3,*

1 Molecular and Cellular Oncology/Mainz Screening Center, University Hospital of Mainz, Germany

2 Institute for Molecular Biology, Centre for Medical Biotechnology (ZMB), University Duisburg-Essen, Germany

3 Institute of Biochemistry and Biophysics/Center for Molecular Biomedicine, Friedrich-Schiller-University Jena, Germany

4 Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, Germany

* Denotes equal contribution

Received: January 16, 2012; Accepted: January 25, 2012; Published: January 28, 2012;

Keywords: BH3-only protein, chemotherapy resistance, hydroxyurea, oral cancer, tumor xenograft, valproic acid

Correspondence:

Oliver H. Krämer, email:

Roland H. Stauber, email:

Shirley K. Knauer, email:

Abstract

Head and neck squamous cell carcinomas (HNSCCs) are the sixth most common malignant neoplasm and more than 50% of patients succumb to this disease. HNSCCs are characterized by therapy resistance, which relies on the overexpression of anti-apoptotic proteins and on the aberrant regulation of the epidermal growth factor receptor (EGFR). As inherent and acquired resistance to therapy counteracts improvement of long-term survival, novel multi-targeting strategies triggering cancer cell death are urgently required. We investigated how induction of replicational stress by the ribonucleotide reductase inhibitor hydroxyurea (HU) combined with histone deacetylase inhibitors (HDACi) exerts anti-tumor activity. We treated HNSCC cell lines and freshly isolated tumor cells with HDACi, such as the clinically approved anti-epileptic drug valproic acid (VPA), in combination with HU. Our data demonstrate that at clinically achievable levels VPA/HU combinations efficiently block proliferation as well as clonogenic survival, and trigger apoptosis of HNSCC cells. In the presence of VPA/HU, such tumor cells increase expression of the pro-apoptotic BCL-2 family protein BIM, independent of wild-type p53 signaling and in the absence of increased expression of the p53 targets PUMA and BAX. The pro-apoptotic activity of BIM in HNSCCs was found critical for tumor cell death; ectopic overexpression of BIM induced HNSCC apoptosis and RNAi-mediated depletion of BIM protected HNSCC cells from VPA/HU. Also, significantly elevated BIM levels (p<0.01) were detectable in the apoptotic tumor centers versus proliferating tumor margins in HNSCC patients (n=31), underlining BIM’s clinical relevance. Importantly, VPA/HU treatment additionally reduces expression and cell surface localization of EGFR. Accordingly, in a xenograft mouse model, VPA/HU efficiently blocked tumor growth (P<0.001) correlating with BIM induction and EGFR downregulation. We provide a molecular rationale for the potent anti-cancer activities of this drug combination. Our data suggest its exploitation as a potential strategy for the treatment of HNSCC and other tumor entities characterized by therapy resistance linked to dysregulated EGFR activation.


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