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

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

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

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.

Highlights

► We show that Cathepsin S is upregulated in colorectal tumour cells by chemotherapy. ► Inhibition of Cathepsin S with Fsn0503 enhances the efficacy of chemotherapy. ► Cathepsin S inhibitors may have clinical utility in chemotherapy regimes.

Original languageEnglish
Pages (from-to)487-493
Number of pages7
JournalBiochimie
Volume94
Issue number2
Early online date31 Aug 2011
DOIs
Publication statusPublished - Feb 2012

    Fingerprint

Cite this