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

Discussion

In this work, a complex in vivo model of tumors accompanied by surgical wound infection was applied. Bacteriophages modified with anticancer YIGSR peptides acted as the active agents. Evaluation of simultaneous anticancer and antibacterial activity of these bacteriophages revealed that both activities were demonstrated. Tumor growth was decreased in mice treated with YIGSR-displaying phages which correlated with phage accumulation in tumors. In the same mice, wounds infected with bacteria but not treated with phages were in significantly worse condition in comparison to those subjected to phage treatment. This worse condition was correlated with the higher bacterial load in the wound and with the higher systemic levels of inflammatory markers.

These observations show the possibility of combination of anticancer (engineered) and antibacterial (natural) phage activity in therapies. Bacterial viruses are proposed as drug carriers and/or display platforms for various anticancer agents;[5,6] their use in novel strategies of anticancer treatment probably offers more than anticancer tools. At the same time they may act as infection preventing or combating agents.

In this work, bacteriophages were used before the surgery, so prevention is one of the mechanisms that may contribute to the final effect. Importantly, phages were applied systemically (ip.), while the infection was located in a wound, but the beneficial effect of bacteriophages was still observed. This is in line with other studies that document good penetration of phages in mammalian tissues and organs,[25] which can be of relevance for the applicability of this combined activity in other locations of tumors and infections.

One of limitations of this study that must be noticed is the fact that murine models cannot be directly transferred to human patients. Mice are known to differ in some elements of cancer processes as well as in their reactions to inflammation (e.g., other type of LPS receptors is engaged in the response at the molecular level). Also the type of tumor: the murine mammary gland cancer is a selected model while we bear in mind the multiplicity of possible cancer disease types. However, this model offered a good example of effective combination of anticancer and antibacterial activity exerted by engineered bacteriophages. Future studies of this activity should include human cancer cell lines, which will enable studies that are closer to human, as well as studies of other types of tumors. A further limitation for the beneficial 'additional antibacterial effects' of phage particles used as carriers is their specificity. Bacteriophages are usually highly specific, which allows the phage to counteract only infections caused by sensitive bacteria. Eventually, prevention of infection in patients will be limited. The range of this limitation will be to some extend related to the range of a particular phage used as a display platform, since bacteriophages are differentiated in the range of their specificity. Here we proposed T4; in the case of T4-like phages this is E. coli and related bacteria. E. coli is also a pathogen responsible for post-surgery infections, including drug-resistant infections. However, in the future other types of bacteriophages used as platforms may widen or change the range of antibacterial protection in cancer patients. In this case, a wide range of antibacterial activity (in comparison to other phage strains) would be a positive designation for a phage as a platform or a carrier.

In addition to the possible antibacterial and anticancer co-activity, this work also contributes to studies of safety aspects in bacteriophage therapy. No negative effects of the use of phages were observed in terms of tumor growth and metastases formation after treatment with neutral (His-modified) bacteriophages. This brings new data on natural phage activity in cancer disease, which further contributes to the prospect of antibacterial use of natural phages in cancer patients. Most life-endangering multidrug-resistant infections are acquired in hospitals and other healthcare units, which often affect cancer patients. Therefore, alternative antibacterial strategies can be useful for this group of patients, both taking into account engineered phages and that of natural ones.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....