Efficacy of Cetuximab and 4-PBA Combination Therapy in Human Oral Squamous Cell Carcinoma Cells

Author(s): Akira Noguchi, Takeshi Nishida, Hideki Hatta, Kohji Takagi, Toshiko Kakiuchi, Shinichi Tanaka, Takashi Minamisaka, Takahiko Nakajima and Johji Imura

Cetuximab is a powerful anti-neoplastic agent that can inhibit cell growth in oral squamous cell carcinomas (OSCCs). Unfortunately, there are cases with unfavorable outcomes. Because few studies have focused on the combined effects of cetuximab and histone deacetylase (HDAC) inhibitors, we aimed to evaluate the antitumor effect of cetuximab in combination with HDAC inhibitors in human OSCC cell lines, and investigate the mechanism of apoptosis enhancing activity thereof. We used human OSCC cell lines treated with cetuximab and several HDAC inhibitors. The WST assay and ApoToxGlo™ Triplex Assay determined cell survival. We employed the TdTmediated dUTP-biotin nick end labeling method to detect apoptosis. We used western blotting to examine the histone acetylation status, ER stress markers, and epidermal growth factor receptor (EGFR) signaling pathways. Our results show that cetuximab in combination with 4-phenyl butyric acid (4-PBA) remarkably decreases cell growth in vitro. In addition, the combined treatment resulted in increased EGFR mRNA expression and promoted the activation of ERK. The combination treatment induced apoptosis at a significantly higher frequency than did either agent alone. In conclusion, the combination of cetuximab and 4-PBA is more effective against human OSCC cells, allowing for potential clinical applicability of combination treatment in OSCC therapies.