Bacteriophages Displaying Anticancer Peptides in Combined Antibacterial and Anticancer Treatment

Krystyna Dąbrowska; Zuzanna Kaźmierczak; Joanna Majewska; Paulina Miernikiewicz; Agnieszka Piotrowicz; Joanna Wietrzyk; Dorota Lecion; Katarzyna Hodyra; Anna Nasulewicz-Goldeman; Barbara Owczarek; Andrzej Górski

Disclosures

Future Microbiol. 2014;9(7):861-869. 

In This Article

Abstract and Introduction

Abstract

Aims: Novel anticancer strategies have employed bacteriophages as drug carriers and display platforms for anticancer agents; however, bacteriophage-based platforms maintain their natural antibacterial activity. This study provides the assessment of combined anticancer (engineered) and antibacterial (natural) phage activity in therapies.

Materials & methods: An in vivo BALB/c mouse model of 4T1 tumor growth accompanied by surgical wound infection was applied. The wounds were located in the areas of tumors. Bacteriophages (T4) were modified with anticancer Tyr–Ile–Gly–Ser–Arg (YIGSR) peptides by phage display and injected intraperitoneally.

Results & conclusion: Tumor growth was decreased in mice treated with YIGSR-displaying phages. The acuteness of wounds, bacterial load and inflammatory markers in phages-treated mice were markedly decreased. Thus, engineered bacteriophages combine antibacterial and anticancer activity.

Introduction

The potential of peptides in cancer treatment is evident due to many studies evolving therapeutic strategies targeting the progression of tumor growth or metastasis formation. Peptides that can target cancer cells or interfere with their functions without affecting normal cells are being developed as an alternate strategy to conventional chemotherapy. Some of them have even entered Phase II clinical trials, becoming promising tools for medicine,[1,2] while others are constantly designed, developed and studied. One of the investigated classes of anticancer peptides are those interfering with adhesive interactions of cancer and normal cells. They are usually derived from extracellular matrix proteins mediating cell adhesion, such as fibronectin or laminin. Systematic screening of peptide motifs within laminin revealed that Tyr–Ile–Gly–Ser–Arg (YIGSR) peptide can substantially decrease tumor growth and experimental metastasis;[3,4] thus, YIGSR represents a group of small but highly active peptides that can be used against cancer.

Dynamic development of novel anticancer strategies has also applied bacteriophages: bacterial viruses are proposed as drug carriers and/or display platforms for various anticancer agents.[5,6] Phage display has become a powerful technology for selecting and amplifying peptides; it is also proposed as a relatively cheap and easy technology for production of active peptides in bulk amounts. Peptides (or proteins) can be presented on the surface of phage capsids as a result of molecular engineering. This may employ introduction of new sequences into the phage genome or incorporation of recombined proteins during capsid assembly.[7–9] The history of phage display started with filamentous phages;[7] later large tailed phages were also employed, for example, T4 phage. T4 phage allows for exposure of both large proteins and small peptides as well as for dual exposure of two different active elements on the same phage.[10,11] Ren et al. showed that the T4 phage display system can be used for anticancer therapy by employment of the VEGF receptor 2 (VEGFR2) and construction of an anticancer vaccine.[12]

At the same time, bacteriophage-based platforms or carriers maintain their natural antibacterial activity that is necessary for phage amplification. Antibacterial activity of phages makes these entities natural enemies of bacteria. Since phages kill bacteria in mechanisms different to those of antibiotics, they can be effective against multidrug-resistant bacterial strains. Nowadays, as we face an emerging problem of antibiotic resistance, bacteriophages are a serious alternative to the insufficient antibacterial arsenal.[13,14] Bacteriophage efficacy has been shown in combating various bacterial infections, including diarrhea, respiratory infections, wounds, urinary tract, bronchitis, otitis media, septicemia, encephalitis and bacterial meningitis, and others.[13–15] However, data on natural phage activity in a wide variety of medical problems are still limited; among those poorly recognized are infections accompanying cancer disease. Most life-endangering multidrug-resistant infections are acquired in hospitals and other healthcare units and cancer patients are often subjected to hospital treatment,[16] including surgery, injection or other invasive treatment. These procedures are related to a serious risk of acquiring drug-resistant bacterial infections. Thus antibacterial activity of bacteriophages may be particularly useful for this group of patients.

These facts raise questions about the possibility of combining anticancer (engineered) and antibacterial (natural) phage activity in therapies. If effective, they can offer a novel strategy for anticancer therapy together with antibacterial protection. Here we present the assessment of such combined treatment in an in vivo model of tumor accompanied by surgical wound infection.

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