A food poisoning bacterium could aid in the fight against multidrug resistant cancers

By Caroline Pearson

Twitter: @CarolineRosePea

Salmonella enterica serovar Typhimurium is a food borne bacterial pathogen that commonly causes gastroenteritis in humans. However, it has been found that this pathogen can selectively grow inside tumours and modulate many biochemical pathways. This resulted in its recognition as a possible tool in the treatment of cancer to deliver therapeutic agents directly to the source of the cancer following systemic infection. Although many applications for this surprisingly therapeutic pathogen have been suggested, translating them into clinical use has been a stumbling point due to the possibility of systemic infections or immune mediated toxic responses to the invading bacteria.

An alternative approach to delivering the live salmonella bacteria to a cancer patient is to identify the therapeutic agents produced by S.Typhimurium which allow it to modulate biochemical pathways and administer these directly to the patient without the risk of systemic Salmonella infection. This approach has been taken by Mercado-Lubo et al., who have identified the molecule responsible for reducing the levels of multidrug resistance (MDR) transporter P-glycoprotein (P-gp) in tumour cells which increases their susceptibility to chemotherapeutic drugs.

Upregulated P-gp expression is associated with poor prognosis in several types of cancer.  The P-gp protein is encoded by MDR1, and is a MDR ABC transporter responsible for one aspect of the MDR phenotype in cancer cells. Recent studies have found that S. Typhimurium was able to reduce levels of P-gp in cancer cells and that the Salmonella type III secretory system was essential for this modulation. Therefore, S. Typhimurium type III secreted effector proteins were screened for their ability to modulate P-gp resulting in the identification of SipA.

SipA is able to modulate P-gp by activation of caspase 3 which then cleaves the P-gp protein so that it can no longer be presented at the cell surface to function as a drug efflux pump.

caroline blog post
Working model of SipA downregulation of P-gp taken from Mercado-Lubo et la., 2016. (a) Cancer cells express different types of ABC transporters, especially P-gp, to gain multidrug resistance. This allows tumour cells to extrude cytotoxic drugs from the intracellular space. (b) The SipA-AuNP may act extracellularly, by interacting with a transmembrane receptor to induce a CASP3 dependent cleavage of P-gp. The activation of caspase-3 also results in apoptosis; a cell death process. (c) Cleavage of P-gp results in the appearance of two protein fragments of about 90 and 60 kDa. Such cleavage destroys the P-gp scaffold essentially removing this transporter from the plasma membrane thereby preventing the active efflux of doxorubicin and enhancing its cytotoxic activity.

To harness the therapeutic potential of this effector protein without having to infect patients with potentially pathogenic S. Typhimurium, Mercado-Lubo et al., built a Salmonella nanoparticle mimic by fusing an inert gold nanoparticle with multiple copies of the SipA protein.  In vitro and in vivo studies both showed that the SipA nanoparticle possessed the ability to reduce P-gp levels in multiple cancer cell lines and increase their susceptibility to treatment with doxorubicin (a chemotherapeutic drug). The nanoparticle structure also enhanced SipA functionality in comparison to free SipA, presumably due to the nanoparticle complex stabilising SipA and preventing its degradation before reaching its target.

The writers suggest that this semi-synthetic Salmonella nanoparticle mimic could be applied to various chemotherapeutic drugs to overcome MDR in tumours and that the findings represent an important step forward in demonstrating the potential of this strategy as a ‘stand alone’ approach to increase cancer cell sensitivity to conventional chemotherapeutics.

 

Source: Mercado-Lubo, R., Zhang, Y., Zhao, L., Rossi, K., Wu, X., Zou, Y., Castillo, A., Leonard, J., Bortell, R. & other authors. (2016). A Salmonella nanoparticle mimic overcomes multidrug resistance in tumours. Nat Commun 7, 12225. Nature Research.

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