Bacterial Drug Efflux Pump Inhibitors from Plants

The high abundance of drug efflux pumps in cancer stem cells (CSCs) contributes to chemotherapy resistance. The transcriptional regulator SMAR1 suppresses CSC expansion in colorectal cancer, and increased abundance of SMAR1 is associated with better prognosis. Here, we found in breast tumors that the expression of SMAR1 was decreased in CSCs through the cooperative interaction of the pluripotency factors Oct4 and Sox2 with the histone deacetylase HDAC1. Overexpressing SMAR1 sensitized CSCs to chemotherapy through SMAR1-dependent recruitment of HDAC2 to the promoter of the gene encoding the drug efflux pump ABCG2. Treating cultured CSCs or 4T1 tumor-bearing mice with the nonsteroidal anti-inflammatory drug aspirin restored SMAR1 expression and ABCG2 repression and enhanced tumor sensitivity to doxorubicin. Our findings reveal transcriptional mechanisms regulating SMAR1 that also regulate cancer stemness and chemoresistance and suggest that, by restoring SMAR1 expression, aspirin might enhance chemotherapeutic efficacy in patients with stem-like tumors.

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An alkylaminoquinazoline restores antibiotic activity in Gram-negative resistant isolates

Microbiology ◽

10.1099/mic.0.045716-0 ◽

2011 ◽

Vol 157 (2) ◽

pp. 566-571 ◽

Cited By ~ 17

Author(s):

Abdallah Mahamoud ◽

Jacqueline Chevalier ◽

Milad Baitiche ◽

Elissavet Adam ◽

Jean-Marie Pagès

Keyword(s):

Efflux Pump ◽

Bacterial Species ◽

Efflux Pumps ◽

Multidrug Resistant ◽

Side Chain ◽

Structural Class ◽

Gram Negative ◽

Activity Spectrum ◽

Efflux Pump Inhibitors ◽

Drug Efflux Pump

To date, various bacterial drug efflux pump inhibitors (EPIs) have been described. They exhibit variability in their activity spectrum with respect to antibiotic structural class and bacterial species. Among the various 4-alkylaminoquinazoline derivatives synthesized and studied in this work, one molecule, 1167, increased the susceptibility of important human-pathogenic, resistant, Gram-negative bacteria towards different antibiotic classes. This 4-(3-morpholinopropylamino)-quinazoline induced an increase in the activity of chloramphenicol, nalidixic acid, norfloxacin and sparfloxacin, which are substrates of the AcrAB-TolC and MexAB-OprM efflux pumps that act in these multidrug-resistant isolates. In addition, 1167 increased the intracellular concentration of chloramphenicol in efflux pump-overproducing strains. The rate of restoration depended on the structure of the antibiotic, suggesting that different sites in the efflux pumps may be involved. A molecule exhibiting a morpholine functional group and a propyl extension of the side chain was more active.

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Identification and Evolution of Drug Efflux Pump in Clinical Enterobacter aerogenes Strains Isolated in 1995 and 2003

PLoS ONE ◽

10.1371/journal.pone.0003203 ◽

2008 ◽

Vol 3 (9) ◽

pp. e3203 ◽

Cited By ~ 36

Author(s):

Jacqueline Chevalier ◽

Céline Mulfinger ◽

Eric Garnotel ◽

Pierre Nicolas ◽

Anne Davin-Régli ◽

...

Keyword(s):

Efflux Pump ◽

Enterobacter Aerogenes ◽

Drug Efflux ◽

Drug Efflux Pump

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The synergistic role of ATP-dependent drug efflux pump and focal adhesion signaling pathways in vinorelbine resistance in lung cancer

Cancer Medicine ◽

10.1002/cam4.1282 ◽

2018 ◽

Vol 7 (2) ◽

pp. 408-419 ◽

Cited By ~ 4

Author(s):

Takao Nakanishi ◽

Toshi Menju ◽

Shigeto Nishikawa ◽

Koji Takahashi ◽

Ryo Miyata ◽

...

Keyword(s):

Lung Cancer ◽

Signaling Pathways ◽

Focal Adhesion ◽

Efflux Pump ◽

Drug Efflux ◽

Drug Efflux Pump

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Modeling of P-glycoprotein-involved epithelial drug transport in MDCK cells

AJP Renal Physiology ◽

10.1152/ajprenal.1999.277.1.f84 ◽

1999 ◽

Vol 277 (1) ◽

pp. F84-F96 ◽

Cited By ~ 6

Author(s):

Shinya Ito ◽

Cindy Woodland ◽

Balázs Sarkadi ◽

Guido Hockmann ◽

Scott E. Walker ◽

...

Keyword(s):

Drug Transport ◽

Diffusion Processes ◽

Efflux Pump ◽

Mdck Cells ◽

Basolateral Membrane ◽

Drug Efflux ◽

Drug Transfer ◽

P Glycoprotein ◽

Drug Efflux Pump ◽

Apical Membranes

P-glycoprotein (P-gp) on the apical membranes of epithelial cells is known as a drug efflux pump. However, unclear is its integral quantitative role in the overall epithelial drug transfer, which also involves distinct diffusion processes in parallel and sequence. We used a simple three-compartment model to obtain kinetic parameters of each drug transfer mechanism, which can quantitatively describe the transport time courses of P-gp substrates, digoxin and vinblastine, across P-gp-expressing MDCK cell monolayers grown on permeable filters. Our results show that the model, which assumes a functionally single drug efflux pump in the apical membrane with diffusion across two membranes and intercellular junctions, is the least complex model with which to quantitatively reproduce the characteristics of the data. Interestingly, the model predicts that the MDCK apical membranes are less diffusion permeable than the basolateral membrane for both drugs and that the distribution volume of vinblastine is 10-fold higher than that of digoxin. Additional experiments verified these model predictions. The modeling approach is feasible to quantitatively describe overall kinetic picture of epithelial drug transport. Further model refinement is necessary to incorporate other modes of drug transport such as transcytosis. Also, whether P-gp solely accounts for the pump function in this model awaits more studies.

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