Multidrug resistance (MDR) in cancer cells can significantly attenuate the response to chemotherapy and increase the likelihood of mortality. The major mechanism involved in conferring MDR is the overexpression of ATP-binding cassette (ABC) transporters, which can increase efflux of drugs from cancer cells, thereby decreasing intracellular drug concentration. Modulators of ABC transporters have the potential to augment the efficacy of anticancer drugs. This editorial highlights some major findings related to ABC transporters and current strategies to overcome MDR.
ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette Transporters ; antagonists & inhibitors ; metabolism ; ATP-Binding Cassette, Sub-Family B, Member 1 ; antagonists & inhibitors ; metabolism ; Antineoplastic Agents ; therapeutic use ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Humans ; Molecular Targeted Therapy ; Multidrug Resistance-Associated Proteins ; antagonists & inhibitors ; metabolism ; Nanomedicine ; Neoplasm Proteins ; antagonists & inhibitors ; metabolism ; Neoplasms ; drug therapy ; metabolism ; Protein-Tyrosine Kinases ; antagonists & inhibitors

Poloxamers are found to be an efficient adjuvant with multiple effects and are applied generally in pharmaceutical field. In recent years, it is investigated that poloxamers can increase the permeability of a broad spectrum of drugs through blood-brain barrier (BBB) by means of manifold mechanisms included: (1) inhibiting P-glycoprotein and multidrug-resistance associated protein efflux systems on BBB; (2) adsorbing different apolipoproteins in plasma on the surface of poloxamer-coated nanoparticles, which could interact with BBB through different receptors and mechanisms; (3) connecting to specific ligands and monoclonal antibodies to cross the BBB via specific endogenous transporters localized within the brain capillary endothelium. Significant roles of poloxamer in drug transport across BBB are considered in this review which provides for important guidance to the design of brain-targeted drug delivery system.
ATP Binding Cassette Transporter, Sub-Family B ; antagonists & inhibitors ; metabolism ; ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette Transporters ; antagonists & inhibitors ; metabolism ; Animals ; Blood-Brain Barrier ; drug effects ; metabolism ; Brain ; metabolism ; Drug Carriers ; Drug Delivery Systems ; Excipients ; pharmacology ; Glucose Transport Proteins, Facilitative ; antagonists & inhibitors ; metabolism ; Humans ; Monocarboxylic Acid Transporters ; antagonists & inhibitors ; metabolism ; Multidrug Resistance-Associated Proteins ; antagonists & inhibitors ; metabolism ; Nanoparticles ; Permeability ; Poloxamer ; chemistry ; pharmacology

ATP-binding cassette (ABC) transporters are a family of proteins that mediate multi-drug resistance (MDR) via ATP-dependent drug efflux pumps. Abnormally expression and function would result in tumor MDR. That is the most important mechanism of MDR. The inhibition of ABC transporters as a strategy to reverse MDR in cancer has been studied extensively. In this review, we reviewed the structure and function of ABC transporters, and focused on the research advances in the mechanism of tumors MDR mediated by ABC transporters and the development of their modulators and reversal strategies.
ATP-Binding Cassette Transporters ; antagonists & inhibitors ; chemistry ; metabolism ; physiology ; Antineoplastic Agents ; therapeutic use ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Humans ; Neoplasms ; drug therapy ; physiopathology

Breast cancer resistance protein (BCRP)/ATP-binding cassette subfamily G member 2 (ABCG2) is an ATP-binding cassette (ABC) transporter identified as a molecular cause of multidrug resistance (MDR) in diverse cancer cells. BCRP physiologically functions as a part of a self-defense mechanism for the organism; it enhances elimination of toxic xenobiotic substances and harmful agents in the gut and biliary tract, as well as through the blood-brain, placental, and possibly blood-testis barriers. BCRP recognizes and transports numerous anticancer drugs including conventional chemotherapeutic and targeted small therapeutic molecules relatively new in clinical use. Thus, BCRP expression in cancer cells directly causes MDR by active efflux of anticancer drugs. Because BCRP is also known to be a stem cell marker, its expression in cancer cells could be a manifestation of metabolic and signaling pathways that confer multiple mechanisms of drug resistance, self-renewal (stemness), and invasiveness (aggressiveness), and thereby impart a poor prognosis. Therefore, blocking BCRP-mediated active efflux may provide a therapeutic benefit for cancers. Delineating the precise molecular mechanisms for BCRP gene expression may lead to identification of a novel molecular target to modulate BCRP-mediated MDR. Current evidence suggests that BCRP gene transcription is regulated by a number of trans-acting elements including hypoxia inducible factor 1α, estrogen receptor, and peroxisome proliferator-activated receptor. Furthermore, alternative promoter usage, demethylation of the BCRP promoter, and histone modification are likely associated with drug-induced BCRP overexpression in cancer cells. Finally, PI3K/AKT signaling may play a critical role in modulating BCRP function under a variety of conditions. These biological events seem involved in a complicated manner. Untangling the events would be an essential first step to developing a method to modulate BCRP function to aid patients with cancer. This review will present a synopsis of the impact of BCRP-mediated MDR in cancer cells, and the molecular mechanisms of acquired MDR currently postulated in a variety of human cancers.
ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette Transporters ; antagonists & inhibitors ; metabolism ; physiology ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Gene Expression Regulation, Neoplastic ; Humans ; Neoplasm Proteins ; antagonists & inhibitors ; metabolism ; physiology ; Neoplasms ; metabolism ; Neoplastic Stem Cells ; metabolism ; Phosphatidylinositol 3-Kinases ; metabolism ; Protein-Tyrosine Kinases ; antagonists & inhibitors ; Proto-Oncogene Proteins c-akt ; metabolism ; Signal Transduction ; Substrate Specificity

Recently, a large number of tyrosine kinase inhibitors(TKIs) have been developed as anticancer agents. These TKIs can specifically and selectively inhibit tumor cell growth and metastasis by targeting various tyrosine kinases and thereby interfering with cellular signaling pathways. The therapeutic potential of TKIs has been hindered by multidrug resistance(MDR), which is commonly caused by overexpression of ATP-binding cassette(ABC) membrane transporters. Interestingly, some TKIs have also been found to reverse MDR by directly inhibiting the function of ABC transporters and enhancing the efficacy of conventional chemotherapeutic drugs. In this review, we discuss ABC transporter-mediated MDR to TKIs and MDR reversal by TKIs.
ATP-Binding Cassette Transporters ; antagonists & inhibitors ; physiology ; Antineoplastic Agents ; pharmacology ; Drug Resistance, Multiple ; drug effects ; Drug Resistance, Neoplasm ; drug effects ; Humans ; Neoplasms ; drug therapy ; Protein Kinase Inhibitors ; pharmacology ; Protein-Tyrosine Kinases ; antagonists & inhibitors

ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette Transporters ; antagonists & inhibitors ; genetics ; Adenoviridae ; genetics ; Breast Neoplasms ; therapy ; Cell Line, Tumor ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Gene Silencing ; Humans ; Mitoxantrone ; pharmacokinetics ; Neoplasm Proteins ; antagonists & inhibitors ; genetics ; RNA Interference ; RNA, Small Interfering ; pharmacology

OBJECTIVETo observe the effects of soluble epoxide hydrolase inhibitor t-AUCB on foam cell formation and cholesterol efflux in macrophage.

METHODSMouse macrophages RAW264.7 were cultured and stimulated with ox-LDL (80 µmol/L) in the absence (group A) or presence of t-AUCB (1, 10, 50, 100 µmol/L, group B) or t-AUCB (100 µmol/L) pretreated with PPARγ antagonist GW9662 (5 µmol/L, group C). The foam cell was identified by oil red O staining. The cholesterol efflux rates of (3)H-cholesterol in cells were measured by liquid scintillation counter. mRNA and protein expressions of ABCA1 were detected by real-time PCR or Western blot, respectively.

RESULTSOil red O staining showed that t-AUCB (100 µmol/L) significantly inhibited foam cell formation which could be significantly reversed by GW9662 (all P < 0.05). t-AUCB dose-dependently increased cholesterol efflux rates in mouse macrophage [(5.91 ± 0.18)% in group A, (7.03 ± 0.33)%, (8.05 ± 0.32)%, (9.04 ± 0.14)%, (10.06 ± 0.85)% in 1, 10, 50, 100 µmol/L t-AUCB groups, all P < 0.05 vs. group A], which could be reversed by pretreatment with GW9662 [(6.33 ± 0.15)% in 100 µmol/L t-AUCB + GW9662 group].t-AUCB also upregulated ABCA1 mRNA and protein expressions in a dose-dependent manner which could be significantly attenuated by pretreatment with GW9662.

CONCLUSIONt-AUCB could inhibit foam cell formation by improving cholesterol efflux through activating PPARγ-ABCA1 pathway in macrophage.

ATP Binding Cassette Transporter 1 ; ATP-Binding Cassette Transporters ; metabolism ; Animals ; Benzoates ; pharmacology ; Cell Differentiation ; drug effects ; Cell Line ; Cholesterol ; metabolism ; Enzyme Inhibitors ; pharmacology ; Epoxide Hydrolases ; antagonists & inhibitors ; Foam Cells ; drug effects ; Macrophages ; cytology ; drug effects ; metabolism ; Mice ; PPAR gamma ; metabolism ; Urea ; analogs & derivatives ; pharmacology

BACKGROUND: Acinetobacter baumannii is one of the most important pathogens capable of colonization in burn patients, leading to drug-resistant wound infections. This study evaluated the distribution of the AdeABC efflux system genes and their relationship to ciprofloxacin resistance in A. baumannii isolates collected from burn patients. METHODS: A total of 68 A. baumannii clinical strains were isolated from patients hospitalized in Motahari Burns Center in Tehran, Iran. Ciprofloxacin susceptibility was tested by the disk diffusion and agar dilution methods. PCR amplification of the adeRS-adeB drug efflux genes was performed for all resistant and susceptible isolates. To assess the role of the drug efflux pump in ciprofloxacin susceptibility, carbonyl cyanide 3-chlorophenylhydrazone (CCCP) was used as an efflux pump inhibitor (EPI). RESULTS: Approximately 95.6% of the Acinetobacter isolates were resistant to ciprofloxacin, with minimum inhibitory concentration (MIC) values ranging from 4 to > or =128 microg/mL. The susceptibility of 86.1% of the resistant isolates increased by factors of 2 to 64 in the presence of CCCP. All resistant isolates were positive for the adeRS-adeB genes, and 73.2% of them had mutations in the AdeRS regulatory system. CONCLUSIONS: The results showed that AdeABC genes are common in A. baumannii, which might be associated with ciprofloxacin non-susceptibility, as indicated by the observed linkage to the presence of the genes essential for the activity of the AdeABC, several single mutations occurring in the adeRS regulatory system, and an increase of ciprofloxacin susceptibility in the presence of a CCCP EPI.
ATP-Binding Cassette Transporters/antagonists & inhibitors/genetics/*metabolism ; Acinetobacter Infections/diagnosis/microbiology ; Acinetobacter baumannii/*drug effects/genetics/isolation & purification ; Anti-Bacterial Agents/*pharmacology ; Bacterial Proteins/antagonists & inhibitors/genetics/*metabolism ; Base Sequence ; Ciprofloxacin/*pharmacology ; DNA, Bacterial/chemistry/genetics/metabolism ; Drug Resistance, Bacterial ; Humans ; Hydrazones/pharmacology ; Microbial Sensitivity Tests ; Mutation ; Polymerase Chain Reaction

Drug resistant bacteria is an increasingly urgent challenge to public health. Bacteria adaptation and extensive abuse of antibiotics contribute to this dilemma. Active efflux of antibiotics is employed by the bacteria to survive the antibiotic pressure. Efflux pump is one of the hot spots of current drug related studies and ideal targets for the improvement of treatment. The efflux pumps and related mechanisms of action, regulation of expression and methodologies were summarized. Comparative genomics analyses were employed to elucidate the underlying mechanisms of action and evolution of efflux pump as exemplified by the Mycobacterium in our lab, which is a crucial re-emerging threat to global public health. The pathway and state-of-art drug development of efflux pump related drugs are included too.
ATP-Binding Cassette Transporters ; antagonists & inhibitors ; drug effects ; physiology ; Anti-Bacterial Agents ; metabolism ; pharmacology ; Bacteria ; metabolism ; Drug Resistance, Multiple, Bacterial ; drug effects ; genetics ; Ion Pumps ; antagonists & inhibitors ; drug effects ; physiology ; Membrane Transport Proteins ; drug effects ; physiology ; Multidrug Resistance-Associated Proteins ; drug effects ; physiology ; Mycobacterium ; metabolism

S1-M1-80 cells, derived from human colon carcinoma S1 cells, are mitoxantrone-selected ABCG2-overexpressing cells and are widely used in in vitro studies of multidrug resistance(MDR). In this study, S1-M1-80 cell xenografts were established to investigate whether the MDR phenotype and cell biological properties were maintained in vivo. Our results showed that the proliferation, cell cycle, and ABCG2 expression level in S1-M1-80 cells were similar to those in cells isolated from S1-M1-80 cell xenografts (named xS1-M1-80 cells). Consistently, xS1-M1-80 cells exhibited high levels of resistance to ABCG2 substrates such as mitoxantrone and topotecan, but remained sensitive to the non-ABCG2 substrate cisplatin. Furthermore, the specific ABCG2 inhibitor Ko143 potently sensitized xS1-M1-80 cells to mitoxantrone and topotecan. These results suggest that S1-M1-80 cell xenografts in nude mice retain their original cytological characteristics at 9 weeks. Thus, this model could serve as a good system for further investigation of ABCG2-mediated MDR.
ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette Transporters ; antagonists & inhibitors ; metabolism ; Adenosine ; analogs & derivatives ; pharmacology ; Animals ; Antineoplastic Agents ; pharmacology ; Cell Cycle ; Cell Line, Tumor ; Cell Proliferation ; Cell Survival ; drug effects ; Cisplatin ; pharmacology ; Colonic Neoplasms ; metabolism ; pathology ; Diketopiperazines ; Doxorubicin ; metabolism ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Female ; Heterocyclic Compounds, 4 or More Rings ; Humans ; Inhibitory Concentration 50 ; KB Cells ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mitoxantrone ; pharmacology ; Neoplasm Proteins ; antagonists & inhibitors ; metabolism ; Neoplasm Transplantation ; Rhodamine 123 ; metabolism ; Topotecan ; pharmacology