A Salmonella nanoparticle mimic overcomes multidrug resistance in tumours

Regino Mercado-Lubo, Yuanwei Zhang, Liang Zhao, Kyle Rossi, Xiang Wu, Yekui Zou, Antonio Castillo, Jack Leonard, Rita Bortell, Dale L. Greiner, Leonard D. Shultz, Gang Han () and Beth A. McCormick ()
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Regino Mercado-Lubo: Department of Microbiology and Physiological Systems
Yuanwei Zhang: Department of Biochemistry & Molecular Pharmacology
Liang Zhao: Department of Biochemistry & Molecular Pharmacology
Kyle Rossi: Department of Microbiology and Physiological Systems
Xiang Wu: Department of Biochemistry & Molecular Pharmacology
Yekui Zou: Department of Biochemistry & Molecular Pharmacology
Antonio Castillo: Department of Microbiology and Physiological Systems
Jack Leonard: Department of Microbiology and Physiological Systems
Rita Bortell: Program in Molecular Medicine, University of Massachusetts Medical School
Dale L. Greiner: Program in Molecular Medicine, University of Massachusetts Medical School
Leonard D. Shultz: The Jackson Laboratory
Gang Han: Department of Biochemistry & Molecular Pharmacology
Beth A. McCormick: Department of Microbiology and Physiological Systems

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract Salmonella enterica serotype Typhimurium is a food-borne pathogen that also selectively grows in tumours and functionally decreases P-glycoprotein (P-gp), a multidrug resistance transporter. Here we report that the Salmonella type III secretion effector, SipA, is responsible for P-gp modulation through a pathway involving caspase-3. Mimicking the ability of Salmonella to reverse multidrug resistance, we constructed a gold nanoparticle system packaged with a SipA corona, and found this bacterial mimic not only accumulates in tumours but also reduces P-gp at a SipA dose significantly lower than free SipA. Moreover, the Salmonella nanoparticle mimic suppresses tumour growth with a concomitant reduction in P-gp when used with an existing chemotherapeutic drug (that is, doxorubicin). On the basis of our finding that the SipA Salmonella effector is fundamental for functionally decreasing P-gp, we engineered a nanoparticle mimic that both overcomes multidrug resistance in cancer cells and increases tumour sensitivity to conventional chemotherapeutics.

Date: 2016
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DOI: 10.1038/ncomms12225

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