Effects of CRM197, a specific inhibitor of HB-EGF, in oral cancer

Abstract

CRM197, a nontoxic mutant of diphtheria toxin, is a specific inhibitor of heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), which belongs to the EGF family that has been implicated in the increased progression, proliferation, and metastasis of oral cancer. In this study, we analyzed the antitumor effects of CRM197, which represent possible chemotherapeutic agents for oral cancer. In the experiment, we used the oral squamous cell carcinoma cell lines HSC3 and SAS. Cells treated with CRM197 were analyzed based on cell viability, MTT assay, invasion assay, Western blot, and zymography. HSC3 cells were injected subcutaneously into female BALB/c nu/nu mice at 5 weeks of age. CRM197 and/or CDDP were injected intraperitoneally into tumor-bearing mice, and tumor volume was measured over time. HB-EGF expression in HSC3 and SAS cells treated with CRM197 was significantly reduced and cell proliferation was inhibited. The invasiveness of CRM197-treated cells was relatively low. MMP-9 and VEGF were suppressed in HSC3 treated with CRM197 on zymography and Western blot. Further, tumor growth in xenografted mice was suppressed by CRM197 or CDDP at 1 mg/kg/day. Also, the coadministration of CDDP and CRM197 at 1 mg/kg/day completely inhibited tumor formation. These results suggest that HB-EGF is a target for oral cancer and that CRM197 is effective in oral cancer therapy.

Macrophages Regulate the Systemic Response to DNA Damage by a Cell Nonautonomous Mechanism

“…Collectively, these data demonstrate that HB-EGF is predominantly expressed by resident kupffer cells and by macrophages recruited to DEN-treated livers, and are consistent with previous data showing that HB-EGF mRNA levels increased primarily in kuppfer cells after partial liver hepatectomy but not in hepatocytes (41). Cross-reacting material 197 (CRM197) is a diphtheria toxin mutant that binds directly to the EGF-like domain of HB-EGF and represses its activity (42,43). Notably, mice treated with CRM197 exhibited significant increase in residual DSB 6 days after DEN injection as compared with control mice (Fig.…”

Notch increases the shedding of HB-EGF by ADAM12 to potentiate invadopodia formation in hypoxia

“…Soluble HB-EGF increased the number of cells forming invadopodia, and inhibition of HB-EGF by CRM-197 reverted the effect. Consistent with a positive role of HB-EGF in tumor progression, different studies describe the antitumoral effects of CRM-197 (Dateoka et al, 2012; Tang et al, 2012). HB-EGF is likely to affect invadopodia formation through binding to EGFR because Gefitinib inhibited the increase in invadopodia formation induced by hypoxia.…”

FAK deletion accelerates liver regeneration after two-thirds partial hepatectomy

“…Therefore, Fak deficiency in hepatocytes may enhance EGFR activation through increasing HB-EGF expression after 2/3 PHx. To test this hypothesis, we treated Fak -deficient mice with CRM197, a specific inhibitor of HB-EGF 23 24 , daily for 3 days starting one day pre-PHx. We found that CRM197 significantly attenuated EGFR activation ( Fig.…”