Salmonella-Based Nanoparticles Suppress Growth of Multidrug Resistant Tumors

Gold nanoparticles were used to transport the Salmonella enterica serotype Typhimurium protein SipA into cancer cells where it decreased the amount of the P-glycoprotein multidrug resistance transporter and suppressed tumor growth.

Salmonella enterica serotype Typhimurium is a food-borne pathogen that also selectively grows in tumors and functionally decreases P-glycoprotein (P-gp), a multidrug resistance transporter. P-glycoprotein pumps waste products, foreign particles, and toxins out of cancer cells and limits the effectiveness of chemotherapeutic drugs. P-gp is a member of a large family of transporters, the ATP-binding cassette (ABC) transporters, that are active in normal cells but also have roles in cancer and other diseases.

By screening a large number of mutant S. typhimurium strains, investigators at the University of Massachusetts Medical School (Worcester, USA) found that the Salmonella type III secretion effector, SipA, was responsible for P-gp modulation through a pathway involving caspase-3.

The investigators capitalized on this finding by attaching SipA to gold nanoparticles, which then functioned as S. Typhimurium mimics. They tested the nanoparticles in a mouse model of colon cancer, since this cancer type expresses high levels of P-gp.

Results published in the July 25, 2016, online edition of the journal Nature Communications revealed that treatment of tumor-bearing mice with the nanoparticles together with the chemotherapeutic agent doxorubicin caused P-gp levels to drop and suppressed tumor growth substantially more than was seen in mice treated with the nanoparticles or doxorubicin alone. The investigators found no evidence of nanoparticle accumulation in the brain, heart, kidney, or lungs of the mice, nor did it appear to cause toxicity. In addition, they found that the nanoparticles were about 100 times more effective than SipA protein alone at reducing P-gp levels in a human colon cancer cell line.

“While trying to understand how Salmonella invades the human host, we made this other observation that may be relevant to cancer therapeutics and multidrug resistance,” said senior author Dr. Beth McCormick, professor of microbiology and physiological systems at the University of Massachusetts Medical School. “Through millions of years of co-evolution, Salmonella has figured out a way to remove this transporter from the surface of intestinal cells to facilitate host infection. We capitalized on the organism’s ability to perform that function. We are not naïve about the complexity of the problem. However, if we know more about the biology, we believe we can ultimately make a better drug.”

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University of Massachusetts Medical School