Colicins and their potential in cancer treatment
Introduction
Cancer remains a major public health problem in the modern world. It is responsible for 250 of 100 000 deaths and 10 million new cases worldwide are diagnosed every year (World Cancer Research Fund international; http://www.wcrf.org). Despite the improvements in surgery, radiotherapy and chemotherapy, these treatments can result in severe side effects or reduced resistance to infection and can have a long-term negative impact on human health (British Cancer agency; http://bccancer.bc.ca/default.htm). Thus, novel, more specific treatments need to be developed in order to add to the therapeutic methods available at present.
One promising strategy to specifically target tumor cells utilizes antibodies that are specific to outer membrane proteins of the cancerous cells and are coupled with cytotoxic compounds such as small-molecule drugs, radionucleotides or protein toxins [1]. Immunotoxins were developed using plant or bacterial toxins that attack eukaryotic cells such as ricin, saponin, diphtheria toxin or Pseudomonas exotoxin. To achieve specific targeting to tumor cells, the natural cell binding domains of the bacterial toxins were deleted or mutated to prevent binding to normal cells, then the toxic domain fused to cell targeting agents such as antibodies, cell-binding hormones, growth factor ligands or transferrin to allow internalisation and, subsequently, cell killing to occur [2]. However, these constructs were found to be highly toxic and the foreign origin of the toxins activated the immune system [3], [4]. Development of milder toxins that are tolerated within humans is required to solve these problems [5].
Bacteriocins produced by bacteria to kill competing bacterial strains could potentially be used as milder toxins against cancerous cells. These proteins are designed to bind the bacterial cell, penetrate the cell wall and kill the cell by a number of methods including pore formation, cleavage of DNA or specific inhibition of protein synthesis. These toxins are not specific for human cell membranes so a targeting system specific for tumor cells would need to be developed. Recent research has shown that the bacteriocins known as colicins can specifically inhibit proliferation of cancer cells, and thus could potentially be explored for combating cancer.
Section snippets
Colicins: an overview
Colicins are a family of antibacterial cytotoxins produced by Escherichia coli and released into the environment during the SOS response. They are present in ∼ 30% of E. coli isolates [6] and are believed to reduce competition from closely related strains of bacteria during times of stress caused by lack of nutrients, UV light or DNA damaging reagents such as mitomycin C. These proteins have been studied extensively in their involvement in competition, diversification and adoption of bacteria.
Cancer targeting by colicins
Research into colicins and their cytotoxic effects with human tumor cells began about 30 years ago, when colicin E3 was first reported to have significant cytocidal effects on human HeLa cells [26]. Some promising results were also observed from a colicin extracted from the E. coli strain HSC10 added to murine ascitic lymphatic leukaemia cells EL-4 [27]. Unfortunately, these results were obtained from a crude extract of colicin and it was soon realised that the anti-neoplastic activity was due
Concluding remarks
When investigating possible therapeutic drugs against cancer, it is important to consider the selectivity, mode of internalisation, intracellular targeting and the role of any form of inhibition within the patient (RNase inhibitors, immune system). Although colicins appear to be a promising group of bacteriocins against cancerous cells, most of these points are still unresolved.
The specificity of colicins for tumor cells is dependent on the colicin and on the cell line used [32]. Generally,
Acknowledgments
This paper is based on a presentation at a Focused Workshop on RNA Chemistry meets Biology sponsored by The Leukemia and Lymphoma Society (Lund, Sweden, September 29–30, 2006). Work in our laboratories was supported by the Deutsche Forschungsgemeinschaft, the Alfried Krupp von Bohlen und Halbach-Stiftung, and the Fonds der Chemischen Industrie.
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