The monoclonal antibody CH12 augments 5-fluorouracil-induced growth suppression of hepatocellular carcinoma xenografts expressing epidermal growth factor receptor variant III.

Abstract

5-Fluorouracil (5-FU) is one of the most common chemotherapeutic agents used for the treatment of hepatocellular carcinoma (HCC). However, chemoresistance has precluded the use of 5-FU alone in clinical regimens. Combination therapies with 5-FU and other anticancer agents are considered to be a therapeutic option for patients with HCC. We previously reported that the expression of epidermal growth factor receptor variant III (EGFRvIII) can decrease the sensitivity of HCC cells to 5-FU. To overcome this problem, in this study, we elucidated the mechanism underlying EGFRvIII-mediated 5-FU resistance. We observed that EGFRvIII expression can induce miR-520d-3p downregulation and the ensuing upregulation of the transcription factor E2F-1 and the enzyme thymidylate synthase (TS), which may lead to drug resistance. Intriguingly, we found that CH12, a monoclonal antibody directed against EGFRvIII, and 5-FU together had an additive antitumor effect on EGFRvIII-positive HCC xenografts and significantly improved survival in all mice with established tumors when compared with either 5-FU or CH12 alone. Mechanistically, compared with 5-FU alone, the combination more noticeably downregulated EGFR phosphorylation and Akt phosphorylation as well as the expression of the apoptotic protector Bcl-xL and the cell cycle regulator cyclin D1. Additionally, the combination upregulated the expression of the cell cycle inhibitor p27 in in vivo treatment. More interestingly, CH12 treatment upregulated miR-520-3p and downregulated E2F-1 and TS at the mRNA and protein levels. Collectively, these observations suggest that the combination of 5-FU with mAb CH12 is a potential means of circumventing EGFRvIII-mediated 5-FU resistance in HCC.

• Authors: Hua Jiang, Qiongna Dong, Xiaoying Luo, Bizhi Shi, Huamao Wang, Huiping Gao, Juan Kong, Jiqin Zhang, Zonghai Li
• Journal: Cancer letters (Cancer Lett) Vol. 342 Issue 1 Pg. 113-20 (Jan 01 2014) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 24007863 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antibodies, Monoclonal
• CH12 monoclonal antibody
• E2F1 Transcription Factor
• E2F1 protein, human
• MIRN520 microRNA, human
• MicroRNAs
• epidermal growth factor receptor VIII
• Dihydrouracil Dehydrogenase (NAD+)
• Thymidylate Synthase
• Orotate Phosphoribosyltransferase
• ErbB Receptors
• Fluorouracil

Topics

• Animals
• Antibodies, Monoclonal (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Apoptosis
• Carcinoma, Hepatocellular (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dihydrouracil Dehydrogenase (NAD+) (metabolism)
• Drug Resistance, Neoplasm
• Drug Synergism
• E2F1 Transcription Factor (genetics, metabolism)
• ErbB Receptors (antagonists & inhibitors, immunology)
• Fluorouracil (administration & dosage)
• Gene Expression
• Gene Expression Regulation, Neoplastic
• Liver Neoplasms (drug therapy, metabolism, pathology)
• Mice
• Mice, Nude
• MicroRNAs (genetics)
• Orotate Phosphoribosyltransferase (metabolism)
• RNA Interference
• Thymidylate Synthase (genetics, metabolism)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays