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The cytotoxic activity of the bacteriophage λ‐holin protein reduces tumour growth rates in mammary cancer cell xenograft models
Author(s) -
Agu Chukwuma A.,
Klein Reinhard,
Schwab Sonja,
KönigSchuster Marielle,
Kodajova Petra,
Ausserlechner Michael,
Binishofer Bernhard,
Bläsi Udo,
Salmons Brian,
Günzburg Walter H.,
Hohenadl Christine
Publication year - 2006
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.833
Subject(s) - biology , cytotoxic t cell , cancer research , microbiology and biotechnology , cancer cell , transfection , cell culture , cancer , in vitro , biochemistry , genetics
Abstract Background The potential use of gene therapy for cancer treatment is being intensively studied. One approach utilises the expression of genes encoding cytotoxic proteins. Such proteins can affect cellular viability, for example by inhibiting the translation machinery or disturbing membrane integrity. The bacteriophage Lambda (λ)‐holin protein is known to form a lesion in the cytoplasmic membrane of E. coli , triggering bacterial cell lysis and thereby enabling the release of new bacteriophage particles. The aim of this study was to evaluate whether the λ‐holin protein has a cytotoxic impact on eukaryotic cells and whether it holds potential as a new therapeutic protein for cancer gene therapy. Methods To explore this possibility, stably transfected human cell lines were established that harbour a tetracycline (Tet)‐inducible system for controlled expression of the λ‐holin gene. The effect of the λ‐holin protein on eukaryotic cells was studied in vitro by applying several viability assays. We also investigated the effect of λ‐holin gene expression in vivo using a human breast cancer cell tumour xenograft as well as a syngeneic mammary adenocarcinoma mouse model. Results The λ‐holin‐encoding gene was inducibly expressed in eukaryotic cells in vitro . Expression led to a substantial reduction of cell viability of more than 98%. In mouse models, λ‐holin‐expressing tumour cell xenografts revealed significantly reduced growth rates in comparison to xenografts not expressing the λ‐holin gene. Conclusions The λ‐holin protein is cytotoxic for eukaryotic cells in vitro and inhibits tumour growth in vivo suggesting potential therapeutic use in cancer gene therapy. Copyright © 2005 John Wiley & Sons, Ltd.