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

2018 ◽  
Vol 7 (2) ◽  
pp. 408-419 ◽  
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

Differential Expression of Resistant and Efflux Pump Genes in MDR-TB Isolates

2020 ◽  
Vol 20 (2) ◽  
pp. 271-287 ◽  
Author(s):  
Manaf AlMatar ◽  
Işıl Var ◽  
Begüm Kayar ◽  
Fatih Köksal
Keyword(s):  
Drug Resistance ◽  
Target Genes ◽  
Efflux Pump ◽  
Gene Mutations ◽  
Clinical Isolates ◽  
Pomegranate Juice ◽  
Drug Efflux ◽  
Mdr Tb ◽  
Drug Efflux Pump

Background: Numerous investigations demonstrate efflux as a worldwide bacterial mode of action which contributes to the resistance of drugs. The activity of antibiotics, which subjects to efflux, can be improved by the combined usage of efflux inhibitors. However, the efflux role to the overall levels of antibiotic resistance of clinical M. tuberculosis isolates is inadequately comprehended and is still disregarded by many. Method: Here, we assessed the contribution of resistant genes associated with isoniazid (INH) and rifampin (R) resistance to the levels of drug resistance in the (27) clinical isolates of MDR-TB. Additionally, the role of the resistance for six putative drug efflux pump genes to the antibiotics was investigated. The level of katG expression was down-regulated in 24/27 (88.88%) of MDR-TB isolates. Of the 27 MDR-TB isolates, inhA, oxyR-ahpC, and rpoB showed either overexpression or up-regulation in 8 (29.62%), 4 (14.81 %), and 24 (88.88%), respectively. Moreover, the efflux pump genes drrA, drrB, efpA, Rv2459, Rv1634, and Rv1250 were overexpressed under INH/RIF plus fresh pomegranate juice (FPJ) stress signifying the efflux pumps contribution to the overall levels of the resistance of MDR-TB isolates. Conclusion: These results displayed that the levels of drug resistance of MDR-TB clinical isolates are due to combination among drug efflux pump and the presence of mutations in target genes, a truth which is often ignored by the specialists of tuberculosis in favour of the almost undoubted significance of drug target- gene mutations for the resistance in M. tuberculosis.

scholarly journals Role of AbeS, a Novel Efflux Pump of the SMR Family of Transporters, in Resistance to Antimicrobial Agents in Acinetobacter baumannii

2009 ◽  
Vol 53 (12) ◽  
pp. 5312-5316 ◽  
Author(s):  
Vijaya Bharathi Srinivasan ◽  
Govindan Rajamohan ◽  
Wondwossen A. Gebreyes
Keyword(s):  
Escherichia Coli ◽  
Acinetobacter Baumannii ◽  
Antimicrobial Agents ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Drug Efflux ◽  
Drug Efflux Pump ◽  
Resistance Expression ◽  
Multidrug Resistant Strain

ABSTRACT In this study, a chromosomally encoded putative drug efflux pump of the SMR family, named AbeS, from a multidrug-resistant strain of Acinetobacter baumannii was characterized to elucidate its role in antimicrobial resistance. Expression of the cloned abeS gene in hypersensitive Escherichia coli host KAM32 resulted in decreased susceptibility to various classes of antimicrobial agents, detergents, and dyes. Deletion of the abeS gene in A. baumannii confirmed its role in conferring resistance to these compounds.

Inhibition of RARα2 or Its Downstream Signaling Pathways Decreases Drug Resistance in Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 989-989
Author(s):  
Guido J. Tricot ◽  
Ye Yang ◽  
Fang Xiao ◽  
Maurizio Zangari ◽  
Hongwei Xu ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Hedgehog Signaling ◽  
Efflux Pump ◽  
Conflicts Of Interest ◽  
Drug Efflux ◽  
Over Expression ◽  
Drug Efflux Pump

Abstract Abstract 989 Background: We have previously reported that the 30% of newly diagnosed myeloma (MM) patients expressing RARα2, had a significantly inferior outcome. RARα2 expression was also significantly increased in rapidly relapsing myelomas compared to paired baseline samples, indicating the existence at diagnosis of a RARα2 subclone, which is drug-resistant. We further demonstrated that RARα2 expression was significantly higher in MM cell line-derived and primary MM stem cells (MMSC) than in CD138+ bulk MM cells. In this study, we further explore the role of RARα2 in myeloma drug resistance. Materials and methods: RARα2 related drug resistance was evaluated by clonogenic formation assays, using 20,000 MM cells from the RARα2 high-expressing ARK and KMS11 MM cell lines, treated with all-trans retinoic acid (ATRA) (1nM, 10nM), Wnt inhibitor CAY10404 (1 nM, 10nM), Hedgehog inhibitor cyclopamine (1nM, 10nM), bortezomib (1nM, 10nM), as well as doxorubicin (50nM, 100nM), etoposide (50nM, 100nM), and verapamil (50nM). To determine whether inhibition of RARa2 decreased drug resistance, 1.0 × 106 KMS11 cells, made resistant to bortezomib, were transfected with RARα2 shRNA and injected subcutaneously into 20 NOD/SCID mice. The 5TGM1 myeloma mice were used to determine whether targeting RARa2 or its signaling pathways could eliminate MMSC. Results: After serial replating for 6 weeks, MMSCs (CD138- fraction) exhibited greater clonogenic expansion than the control CD138+ fraction, while ATRA, an inhibitor of RARα2, induced potent clonogenic inhibition on MMSC. We also showed in vitro that over-expression of RARα2 in low-expressing MM cell lines, ARP1 and OCI-MY5 resulted in increased clonogenic potential and drug-resistance. In a xenograft myeloma mouse model, knockdown of RARα2 in the KSM11bortezomib-resistant cells decreased resistance to bortezomib. We further identified that RARα2 induced drug resistance by activating the drug efflux pump gene ABCC3 through Wnt and Hedgehog signaling. Inhibition of Wnt (CAY10404) signaling or the ABC transporter by verapamil overcame the drug-resistance in ARP1 and OCI-MY5 cells caused by RARα2 over-expression. Finally, targeting RARa2 or its pathways using ATRA, CAY10404 and cyclopamine significantly reduced the tumor burden as determined by idiotype IgG2 protein levels and increased survival compared to untreated controls (P < 0.05) in the 5TGM1 mice after injection of 5TGM1 MMSC. Conclusion: Over-expression of RARa2 induces drug resistance by activating the drug efflux pump gene ABCC3 through activation of the Wnt and Hedgehog pathways, while inhibition of RARα2 decreases drug resistance. We also provide a possible strategy to eliminate MMSC by targeting RARa2 and/or its downstream targets, such as the Wnt and Hedgehog pathways. Disclosures: No relevant conflicts of interest to declare.

Promiscuous partnering and independent activity of MexB, the multidrug transporter protein from Pseudomonas aeruginosa

2010 ◽  
Vol 430 (2) ◽  
pp. 355-364 ◽  
Author(s):  
Alexander Welch ◽  
Chidiebere U. Awah ◽  
Shiheng Jing ◽  
Hendrik W. van Veen ◽  
Henrietta Venter
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Drug Transport ◽  
Efflux Pump ◽  
Multidrug Transporter ◽  
Drug Efflux ◽  
Transporter Protein ◽  
Functional Complex ◽  
Drug Efflux Pump ◽  
Key Questions

The MexAB–OprM drug efflux pump is central to multidrug resistance of Pseudomonas aeruginosa. The ability of the tripartite protein to confer drug resistance on the pathogen is crucially dependent on the presence of all three proteins of the complex. However, the role of each protein in the formation of the intact functional complex is not well understood. One of the key questions relates to the (in)ability of MexB to act independently of its cognitive partners, MexA and OprM. In the present study, we have demonstrated that, in the absence of MexA and OprM, MexB can: (i) recruit AcrA and TolC from Escherichia coli to form a functional drug-efflux complex; (ii) transport the toxic compound ethidium bromide in a Gram-positive organism where the periplasmic space and outer membrane are absent; and (iii) catalyse transmembrane chemical proton gradient (ΔpH)-dependent drug transport when purified and reconstituted into proteoliposomes. Our results represent the first evidence of drug transport by an isolated RND (resistance–nodulation–cell division)-type multidrug transporter, and provide a basis for further studies into the energetics of RND-type transporters and their assembly into multiprotein complexes.

P-glycoprotein as the drug efflux pump in primary cultured bovine brain capillary endothelial cells

Life Sciences ◽  
1992 ◽  
Vol 51 (18) ◽  
pp. 1427-1437 ◽  
Author(s):  
Akira Tsuji ◽  
Tetsuya Terasaki ◽  
Yasushi Takabatake ◽  
Yoshiyuki Tenda ◽  
Ikumi Tamai ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Efflux Pump ◽  
Bovine Brain ◽  
Drug Efflux ◽  
Brain Capillary ◽  
Brain Capillary Endothelial Cells ◽  
P Glycoprotein ◽  
Capillary Endothelial Cells ◽  
Drug Efflux Pump

Structure-property correlation in gallic acid and 4-cyanopyridine cocrystal and binding studies with drug efflux pump in bacteria

2021 ◽  
Vol 1225 ◽  
pp. 129279
Author(s):  
Shyam Goswami ◽  
Arabinda Ghosh ◽  
Karmajyoti Borah ◽  
Anupam Mahanta ◽  
Ankur K Guha ◽  
...  
Keyword(s):  
Gallic Acid ◽  
Efflux Pump ◽  
Drug Efflux ◽  
Structure Property ◽  
Binding Studies ◽  
Property Correlation ◽  
Drug Efflux Pump

scholarly journals Phytochemicals increase the antibacterial activity of antibiotics by acting on a drug efflux pump

2014 ◽  
Vol 3 (6) ◽  
pp. 885-896 ◽  
Author(s):  
Thelma Ohene‐Agyei ◽  
Rumana Mowla ◽  
Taufiq Rahman ◽  
Henrietta Venter
Keyword(s):  
Antibacterial Activity ◽  
Efflux Pump ◽  
Drug Efflux ◽  
Drug Efflux Pump

SMAR1 repression by pluripotency factors and consequent chemoresistance in breast cancer stem-like cells is reversed by aspirin

2020 ◽  
Vol 13 (654) ◽  
pp. eaay6077
Author(s):  
Apoorva Bhattacharya ◽  
Shravanti Mukherjee ◽  
Poulami Khan ◽  
Shruti Banerjee ◽  
Apratim Dutta ◽  
...  
Keyword(s):  
Efflux Pump ◽  
Chemotherapy Resistance ◽  
Cooperative Interaction ◽  
Drug Efflux ◽  
Cancer Stemness ◽  
Gene Encoding ◽  
Pluripotency Factors ◽  
Tumor Bearing ◽  
Drug Efflux Pumps ◽  
Drug Efflux Pump

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.

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

PLoS ONE ◽  
2008 ◽  
Vol 3 (9) ◽  
pp. e3203 ◽  
Author(s):  
Jacqueline Chevalier ◽  
Céline Mulfinger ◽  
Eric Garnotel ◽  
Pierre Nicolas ◽  
Anne Davin-Régli ◽  
...  
Keyword(s):  
Efflux Pump ◽  
Enterobacter Aerogenes ◽  
Drug Efflux ◽  
Drug Efflux Pump

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

1999 ◽  
Vol 277 (1) ◽  
pp. F84-F96 ◽  
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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