Anticancer activity of EMD37 against human head and neck cancer: Impact on apoptotic and inflammatory machineries

Accumulating evidence emphasizes the tumorigenic role of epidermal growth factor receptor (EGFR) in head and neck cancer (HNC). Although cetuximab is the sole anti-EGFR approved by the Food and Drug Administration for treating HNC patients.its response rates are modest. Thus, novel effective and tolerable therapeutic strategies are urged. We previously reported the capability of oxadiazole derivatives to degrade tyrosine kinase receptors including EGFR and exhibit potent anticancer activities against NCI-60 panel which does not include HNC. The aim of this study was to investigate the potential anticancer activity of EMD37, a novel 1,2,4-oxadiazole derivative, against human HNC cells and if effective, to examine the effect of EMD37 on apoptotic and inflammation mediators. Indeed, EMD37 exhibited potent cytotoxicity against patient-derived HNC cell lines (HNO-97, HN-9 and FaDu). Delving deeper, EMD37 triggered intrinsic and extrinsic apoptosis in HNC cells as evidenced by increased levels of caspase-8, caspase-9, caspase-3, caspase-7, caspase-6, TP53BP1 tumor suppressor and Bax, and downregulated anti-apoptotic Bcl-2 protein. EMD37 also significantly abrogated the levels of pro-inflammatory interleukin-1β, interleukin-6, cyclooxygenase-2 and matrix metalloproteinases (MMP-2 and MMP-9) which are heightened in HNC. Bioinformatic analysis revealed that BCL2^low, IL6^low and MMP9^low HNC biospecimens are enriched with epithelial cell differentiation gene set, and CASP8^high cohort is enriched with extrinsic apoptosis. Altogether, this study emphasizes the therapeutic potential of targeting the apoptotic and inflammatory machineries in HNC using EMD37.