Cross-reacting material 197, a heparin-binding EGF-like growth factor inhibitor, reverses the chemoresistance in human cisplatin-resistant ovarian cancer.

Abstract

Cross-reacting material 197 (CRM197), a specific HB-EGF inhibitor, has been proven to be a promising antitumor agent for ovarian cancer therapy. Our previous studies have shown that CRM197 has potent antitumor activity in human cisplatin-resistant ovarian cancer. However, the relationship between CRM197 and the resistance to cisplatin remains unclear. Here, we report that CRM197 significantly reverses the resistance to cisplatin in cisplatin-resistant ovarian carcinoma cell line (A2780/CDDP). We established xenograft nude mice models with A2780 and A2780/CDDP cells. Notably, we observed that CRM197 suppresses the expression of HB-EGF and epidermal growth factor receptor in A2780/CDDP cells and xenografts harboring the overexpression of HB-EGF and epidermal growth factor receptor. Experiments conducted in vitro and in vivo suggest that CRM197 markedly downregulates the expression of excision repair cross-complementing group 1 (P = 0.002) and DNA repair capacity in A2780/CDDP tumor (P < 0.001) by inactivation of extracellular signal-regulated kinase signaling, providing novel possible mechanisms for the ability of CRM197 to restore drug sensitivity. These results suggest that CRM197 as an HB-EGF inhibitor might be a cisplatin-chemosensitizing agent for the treatment of ovarian carcinoma with resistance to cisplatin.

• Authors: Xiao-Han Tang, Meng Li, Suo Deng, Mei-Song Lu
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 25 Issue 10 Pg. 1201-10 (Nov 2014) ISSN: 1473-5741 [Electronic] England
• PMID: 25115341 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Bacterial Proteins
• DNA-Binding Proteins
• Heparin-binding EGF-like Growth Factor
• CRM197 (non-toxic variant of diphtheria toxin)
• EGFR protein, human
• ErbB Receptors
• Extracellular Signal-Regulated MAP Kinases
• ERCC1 protein, human
• Endonucleases
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Bacterial Proteins (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cisplatin (pharmacology, therapeutic use)
• DNA-Binding Proteins (metabolism)
• Drug Resistance, Neoplasm (drug effects)
• Endonucleases (metabolism)
• ErbB Receptors (metabolism)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Heparin-binding EGF-like Growth Factor (metabolism)
• Humans
• Mice, Inbred BALB C
• Mice, Nude
• Ovarian Neoplasms (drug therapy, metabolism, pathology)