Does dexamethasone inhibit anticancer activity of cetuximab in squamous cell carcinoma cell lines of the head and neck?

Abstract

Abstract. Glucocorticoids such as dexamethasone are widely used as comedication in the treatment of head and neck cancer, e.g., to improve appetite and decrease weight loss and fatigue in patients with advanced disease or as antiallergic and antiemetic prophylaxis during anti-EGFR therapy. However, the literature suggests that dexamethasone induces resistance to antineoplastic agents in many solid tumor models in vitro and in vivo. Since this phenomenon has never been investigated in head and neck cancer, the present study was conducted to investigate the effect of dexamethasone on the antiproliferative activity of cetuximab in vitro in squamous cell carcinoma of the head and neck (SCCHN) cell lines. The antiproliferative effect of the anti-EGFR agent cetuximab alone and in combination with increasing concentrations of dexamethasone was examined in eight SCCHN cell lines at three different time-points (24, 48 and 72 h). Cell growth inhibition and viability were measured quantitatively using WST and LDH assays. Absolute tumor cell numbers were determined by cell counting in a Rosenthal chamber. Cetuximab alone inhibited the growth of all eight SCCHN cell lines significantly (p=0.008). In some cases the addition of dexamethasone reduced the antiproliferative activity of cetuximab (p≤0.038) but remained significant in all of the eight SCCHN cell lines compared with untreated controls (p≤0.028) at each drug concentration and each time-point. In contrast to the results reported for other tumor models, in our study dexamethasone showed in the majority of the evaluated dexamethasone drug concentrations and timepoints no inhibition of the cytotoxic activity of cetuximab. The reasons for these discrepant findings are unclear but may be related to the degree of tumor cell differentiation or proliferation rate. Thus, further studies are required to elucidate the molecular mechanisms underlying the interaction between dexamethasone and cetuximab in different tumors.

Assessment of the change in cetuximab‐induced antibody‐dependent cellular cytotoxicity activity of natural killer cells by steroid

“…Similarly, 100 ng/mL of dexamethasone completely suppressed NK cell ADCC activity against colon cancer cells (data not shown). Contrary to previous reports, cetuximab alone could not show tumoricidal activity in our experiments (data not shown). Because this discrepancy might be due to the short incubation period, this result suggests the importance of NK cells in treating cancer with a therapeutic antibody.…”

“…Steroids have been reported to reduce NK cell numbers and cytotoxic T cells, both of which could attack tumor cells by inducing apoptosis. 10 Because we could not detect the decrease of NK cell numbers by a clinically relevant concentration of dexamethasone, the short period of in vitro microculture in this experiment may explain this discrepancy.…”

“…Many reports suggested that steroid therapy interferes with the NK cell activity, but the relationship between steroids and NK cell ADCC activity under tumor environment has not been elucidated. Before examining the effect of steroids over cetuximab‐mediated ADCC activity, we assessed whether EGFR expression on tumor cells is changed by cetuximab because the activity of cetuximab is relied on the EGFR expression level .…”

“…Therefore, it is worthwhile to note that, in the present study, clinically relevant concentration of dexamethasone was sufficient to attenuate cetuximab‐induced NK cells ADCC activity. Although Wagenblast et al has described that the antiproliferative effect of cetuximab against HNSCC is not diminished by dexamethasone, their study compared the relationship between cetuximab and dexamethasone against tumor without bystander cells. In our preliminary study, EGFR TKI receptor (gefitinib or erlotinib) strongly inhibited tumor cells but cetuximab could not show evident cytotoxicity without NK cells (data not shown).…”

Dexamethasone Reduces Sensitivity to Cisplatin by Blunting p53-Dependent Cellular Senescence in Non-Small Cell Lung Cancer

“…Using cell counting, CCK-8 assay and Cell IQ detection, our results corresponded to these reports showing that DEX partially reverses chemotherapy effect not only in NSCLC cell lines but also in tumor xenografts. Also, there in contrast existed a study which focused on the head and neck cancer showing that DEX had no inhibition of the cytotoxic activity of cetuximab in cell lines [28]. The reasons for the findings may be related to intrinsic properties of specific tumor cells and suggested a more cell type-specific effect of glucocorticoids should be studied.…”