Dual Targeting of the p38 MAPK-HO-1 Axis and cIAP1/XIAP by Demethoxycurcumin Triggers Caspase-Mediated Apoptotic Cell Death in Oral Squamous Cell Carcinoma Cells

Abstract

Demethoxycurcumin (DMC) is an 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, an 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 an role for DCM as part of an therapeutic approach for OSCC through suppressing IAPs and activating the p38-HO-1 axis.

MCU That Is Transcriptionally Regulated by Nrf2 Augments Malignant Biological Behaviors in Oral Squamous Cell Carcinoma Cells

“…Furthermore, most of patients have high drug resistance and cytotoxicity. Thus, the prognosis of OSCC is still very poor, with a five-year survival rate of <50% [ 8 ]. Therefore, it is of great significance for OSCC treatment to find markers with molecular diagnosis, prognosis prediction, and targeted therapy.…”

The Curcumin Analogue, EF-24, Triggers p38 MAPK-Mediated Apoptotic Cell Death via Inducing PP2A-Modulated ERK Deactivation in Human Acute Myeloid Leukemia Cells

“…MAPK signaling pathways, including the c-Jun N-terminal kinase 1/2 (JNK1/2) and p38 MAPK, were reported to be involved in the caspase-mediated apoptotic effect triggered by CUR or DMC in various cancer types [ 26 , 27 , 28 ]. We therefore examined whether EF-24 could influence the activation of MAPKs, and observed the dynamic changes in MAPK activities in response to treatment with different concentrations of EF-24 ( Figure 3 A).…”

Morusin Suppresses Cancer Cell Invasion and MMP-2 Expression through ERK Signaling in Human Nasopharyngeal Carcinoma

“…To evaluate the cytotoxicity of morusin (No. CFN97083, Purity ≥ 98%, ChemFaces Biochemical Co., Ltd. Wuhan, China), microculture tetrazolium (MTT) colorimetric assay was performed to determine cell viability, as previously described [ 37 ]. After Formazan formed, and the samples were measured spectrophotometrically (Bio-Tek Instruments, Winooski, VT, USA) at 570 nm.…”