Inflammation is a central aspect of tumour biology and can contribute significantly to both the origination and progression of tumours. The NFκB pathway is one of the most important signal transduction pathways in inflammation and is, therefore, an excellent target for cancer therapy. In this work, we examined the influence of four NFκB inhibitors—Cortisol, MLN4924, QNZ and TPCA1—on proliferation, inflammation and sensitisation to apoptosis mediated by the death ligand FasL in the HNSCC cell lines PCI1, PCI9, PCI13, PCI52 and SCC25 and in the human dermal keratinocyte cell line HaCaT. We found that the selection of the inhibitor is critical to ensure that cells do not respond by inducing counteracting activities in the context of cancer therapy, e.g., the extreme IL-8 induction mediated by MLN4924 or FasL resistance mediated by Cortisol. However, TPCA1 was qualified by this in vitro study as an excellent therapeutic mediator in HNSCC by four positive qualities: (1) proliferation was inhibited at low μM-range concentrations; (2) TNFα-induced IL-8 secretion was blocked; (3) HNSCC cells were sensitized to TNFα-induced cell death; and (4) FasL-mediated apoptosis was not disrupted.

Our study underscores the negative predictive role of MAGE-A11 expression in head and neck cancer.

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Abstract. Inhibitor of apoptosis proteins, which are overexpressed in head and neck squamous cell carcinoma (HNSCC), may cause therapeutic resistance. Using SMAC mimetic compounds, including birinapant, to degrade and/or inhibit these proteins and sensitize apoptosis may enhance therapies in HNSCC. Fas expression was analyzed in nine HNSCC cell lines and one keratinocyte cell line via flow cytometry. These cell lines were treated with Fas ligand-Fc (FasL) and birinapant, a bivalent SMAC mimetic, in mono and combination therapies. Cytotoxicity was measured using a crystal violet assay. Annexin V assay was performed for detection of apoptosis. The treatment efficacy of mono and combination therapies was statistically analyzed. Nonlinear regression analysis was performed to determine the inhibitory concentration (IC 10 ) of birinapant. Fas expression was detected in each cell line tested. Mono treatment with FasL revealed minor to no apoptotic effects in the majority of the cell lines. Crystal violet and Annexin V staining revealed increased apoptosis rates for all cell lines following incubation with birinapant in mono treatment. Combination treatment with FasL and birinapant (IC 10 ) revealed additional and synergistic effects in eight out of the ten cell lines. To the best of our knowledge, the present study provided the first evidence of the apoptosis-sensitizing activity of combination treatment with FasL and birinapant in HNSCC cell lines.

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