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Open Access Research article

Role of nitric oxide in Salmonella typhimurium-mediated cancer cell killing

Yoram Barak15, Frank Schreiber2, Steve H Thorne34, Christopher H Contag3, Dirk deBeer2 and A Matin1*

Author Affiliations

1 Department of Microbiology and Immunology, Sherman Fairchild Science Building, Stanford University School of Medicine, 299 Campus Drive, Stanford, CA 94305, USA

2 Microsensor Research Group, Max Planck Institute for Marine Microbiology, Celsiusstr. 1 D-28359 Bremen, Germany

3 Department of Pediatrics and Bio-X Program, James H. Clark Center, Stanford University School of Medicine, 318 Campus Drive, Stanford, CA 94305, USA

4 Department of Surgical Oncology, Hillman Cancer Center, Centre Avenue, University of Pittsburgh, Pittsburgh, PA 15232, USA

5 Codexis Inc. 200 Penobscot, Redwood City, CA 94063, USA

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BMC Cancer 2010, 10:146  doi:10.1186/1471-2407-10-146

Published: 17 April 2010

Abstract

Background

Bacterial targeting of tumours is an important anti-cancer strategy. We previously showed that strain SL7838 of Salmonella typhimurium targets and kills cancer cells. Whether NO generation by the bacteria has a role in SL7838 lethality to cancer cells is explored. This bacterium has the mechanism for generating NO, but also for decomposing it.

Methods

Mechanism underlying Salmonella typhimurium tumour therapy was investigated through in vitro and in vivo studies. NO measurements were conducted either by chemical assays (in vitro) or using Biosensors (in vivo). Cancer cells cytotoxic assay were done by using MTS. Bacterial cell survival and tumour burden were determined using molecular imaging techniques.

Results

SL7838 generated nitric oxide (NO) in anaerobic cell suspensions, inside infected cancer cells in vitro and in implanted 4T1 tumours in live mice, the last, as measured using microsensors. Thus, under these conditions, the NO generating pathway is more active than the decomposition pathway. The latter was eliminated, in strain SL7842, by the deletion of hmp- and norV genes, making SL7842 more proficient at generating NO than SL7838. SL7842 killed cancer cells more effectively than SL7838 in vitro, and this was dependent on nitrate availability. This strain was also ca. 100% more effective in treating implanted 4T1 mouse tumours than SL7838.

Conclusions

NO generation capability is important in the killing of cancer cells by Salmonella strains.