Inhibition of Cathepsin S by Fsn0503 enhances the efficacy of chemotherapy in colorectal carcinomas.

Abstract

Cathepsin S is a lysosomal cysteine protease implicated in tumourigenesis with key roles in invasion and angiogenesis. We have previously shown that the specific inhibition of Cathepsin S using a monoclonal antibody (Fsn0503) blocks colorectal carcinoma tumour growth and angiogenesis in vivo. We investigated whether Cathepsin S expression levels were affected by chemotherapy in human cancer cell lines by RT-PCR. Using colorectal xenograft models, we examined the therapeutic benefit of Cathepsin S inhibition using Fsn0503 in combination with a metronomic dosing regimen of CPT-11. We analysed the effects of the combination therapy on tumour progression and on tumour vascularisation by immunohistochemical staining of tumours. Cathepsin S expression levels are upregulated in HCT116, LoVo, Colo205 cell lines and HUVECs after exposure to CPT-11 in vitro. The administration of Fsn0503 in combination with CPT-11 significantly attenuated tumour growth in comparison to CPT-11 alone in colorectal HCT116 xenograft models. Furthermore, analysis of tumour vascularisation revealed that this was also significantly disrupted by the combination treatment. These results show that the combination of Cathepsin S inhibition with CPT-11 enhances the therapeutic effect of the chemotherapy. This rationale may have clinical application in the treatment of colorectal cancer upon further evaluation.

• Authors: Roberta E Burden, Julie A Gormley, Diana Kuehn, Claire Ward, Hang Fai Kwok, Mihaela Gazdoiu, Angela McClurg, Thomas J Jaquin, James A Johnston, Christopher J Scott, Shane A Olwill
• Journal: Biochimie (Biochimie) Vol. 94 Issue 2 Pg. 487-93 (Feb 2012) ISSN: 1638-6183 [Electronic] France
• PMID: 21896304 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antibodies, Monoclonal
• Cysteine Proteinase Inhibitors
• Irinotecan
• Cathepsins
• cathepsin S
• Camptothecin

Topics

• Animals
• Antibodies, Monoclonal (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Camptothecin (administration & dosage, analogs & derivatives)
• Cathepsins (antagonists & inhibitors, genetics, metabolism)
• Cell Line, Tumor
• Colon (blood supply, drug effects, pathology)
• Colorectal Neoplasms (drug therapy, enzymology, pathology)
• Cysteine Proteinase Inhibitors (administration & dosage)
• Gene Expression (drug effects)
• Humans
• Irinotecan
• Mice
• Mice, Nude
• Neovascularization, Pathologic
• Treatment Outcome
• Xenograft Model Antitumor Assays