Demethoxycurcumin (DMC) is a curcumin analogue with better stability and higher aqueous solubility than curcumin after oral ingestion and has the potential to treat diverse cancers, including oral squamous cell carcinoma (OSCC). The aim of this study was to investigate the anticancer effects and underlying mechanisms of DMC against OSCC. We found that DMC suppressed cell proliferation via simultaneously inducing G2/M‐phase arrest and cell apoptosis. Mechanistic investigations found that the downregulation of cellular IAP 1 (cIAP1)/X‐chromosome-linked IAP (XIAP) and upregulation of heme oxygenase‐1 (HO‐1) were critical for DMC‐induced caspase‐8/‐9/‐3 activation and apoptotic cell death. Moreover, p38 mitogen‐activated protein kinase (MAPK) and c‐Jun N‐terminal kinase (JNK)1/2 were activated by DMC treatment in OSCC cells, and only the inhibition of p38 MAPK significantly abolished DMC‐induced HO‐1 expression and caspase‐8/‐9/‐3 activation. The analyses of clinical datasets revealed that patients with head and neck cancers expressing high HO‐1 and low cIAP1 had the most favorable prognoses. Furthermore, a combinatorial treatment of DMC with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib, significantly enhanced the inhibitory effect of gefitinib on the proliferation of OSCC cells. Overall, the current study supported a role for DCM as part of a therapeutic approach for OSCC through suppressing IAPs and activating the p38‐HO‐1 axis.
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