Synergistic anti-tumor effect of CDDP with CRM197, a specific inhibitor of HB-EGF, in oral cancer

  • Dateoka Suguru
    Graduate School of Dentistry (Second Department of Oral and Maxillofacial Surgery), Osaka Dental University
  • Ohnishi Yuichi
    Second Department of Oral and Maxillofacial Surgery, Osaka Dental University
  • Kakudo Kenji
    Second Department of Oral and Maxillofacial Surgery, Osaka Dental University

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Abstract

CRM197, a mutated diphtheria toxin (DT), has been found in nontoxic proteins. Because it is non-toxic, this protein has been utilized for various purposes, including as an inhibitor of HB-EGF, which belongs to the EGF family, and has been implicated in the increased progression, proliferation, and metastasis of oral cancer. We analyzed the anti-tumor effects of CRM197 in oral cancer. Inhibitory agents against HB-EGF, such as CRM197, represent possible chemotherapeutic and chemosensitizing agents for oral cancer. In this experiment, we used the oral squamous cell carcinoma cell line HSC3, HSC4, and SAS. Cells treated with CRM197 were analyzed based on cell viability, MTT assay, Western blot, and zymography, following the manufacturers' instructions. Cell proliferation on treatment with CRM197 and/or CDDP was inhibited and apoptosis was observed. The invasiveness of CRM197-treated oral squamous cell carcinoma cells was relatively low. MMP-9 expression on reverse transcription polymerase chain reaction (RT-PCR) revealed that MMP-9 was suppressed in oral squamous cell carcinoma cells treated with CRM197. These results suggest that HB-EGF is a target for cancer therapy. We found that not only is CRM197 effective as a specific inhibitor of HB-EGF, but it also has a synergistic anti-tumor effect when combined with CDDP in oral cancer therapy.

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