Salmonella Overcomes Drug Resistance in Tumor through P-glycoprotein Downregulation.

Abstract

Chemotherapy is one of effective methods for the treatment of tumor. Patients often develop drug resistance after chemotherapic cycles. Salmonella has potential as antitumor agent. Salmonella used in tandem with chemotherapy had additive effects, providing a rationale for using tumor-targeting Salmonella in combination with conventional chemotherapy. To improve the efficacy and safety of Salmonella, a further understanding of Salmonella interactions with the tumor microenvironment is required. The presence of plasma membrane multidrug resistance protein P-glycoprotein (P-gp) is highly relevant for the success of chemotherapy. Following Salmonella infection, dose-dependent downregulation of P-gp expressions were examined. Salmonella significantly decreased the efflux capabilities of P-gp, as based on the influx of Rhodamine 123 assay. In addition, Salmonella significant reduced the protein express the expression levels of phosph-protein kinase B (P-AKT), phosph-mammalian targets of rapamycin (P-mTOR), and phosph-p70 ribosomal s6 kinase (P-p70s6K) in tumor cells. The Salmonella-induced downregulation of P-gp was rescued by transfection of cells with active P-AKT. Our results demonstrate that Salmonella in tumor sites leads to decrease the expression of P-gp and enhances the combination of Salmonella and 5-Fluorouracil therapeutic effects.

• Authors: Chih-Jen Yang, Wen-Wei Chang, Song-Tao Lin, Man-Chin Chen, Che-Hsin Lee
• Journal: International journal of medical sciences (Int J Med Sci) Vol. 15 Issue 6 Pg. 574-579 ( 2018) ISSN: 1449-1907 [Electronic] Australia
• PMID: 29725247 (Publication Type: Journal Article)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• Ribosomal Protein S6 Kinases, 70-kDa
• TOR Serine-Threonine Kinases
• Fluorouracil

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics)
• Animals
• Cell Membrane (drug effects, genetics)
• Combined Modality Therapy
• Drug Resistance, Multiple (genetics)
• Fluorouracil (administration & dosage)
• Gene Expression Regulation, Neoplastic (genetics)
• Humans
• Melanoma, Experimental (drug therapy, microbiology, pathology)
• Mice
• Proto-Oncogene Proteins c-akt (genetics)
• Ribosomal Protein S6 Kinases, 70-kDa (genetics)
• Salmonella (genetics, pathogenicity)
• Salmonella Infections (genetics, microbiology, pathology)
• TOR Serine-Threonine Kinases (genetics)
• Tumor Microenvironment (drug effects)