Suppression of P-glycoprotein by cigarette smoke extract in human lung-derived A549/P-gp cells

Takano, Mikihisa; Higa, Shuhei; Furuichi, Yuma; Naka, Ryosuke; Yumoto, Ryoko

doi:10.1016/j.dmpk.2019.12.001

Cited by 4 publications

(4 citation statements)

References 25 publications

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“…With the growing understanding that drugs and other xenobiotics can cause clinical DDIs via transporter induction 6,108,109 and suppression, 110 it is imperative to incorporate such complexity into physiologically based mathematical models to accurately predict DDI risks (Table 6). To date, the dynamics of NR-mediated transporter regulation has not been systematically studied, and a widely accepted predictive mathematical and/or biology-based model evaluating the dynamics of transporter induction after NR activation and the effects of post-transcriptional or posttranslational modifications is not available.…”

Section: Pharmacokinetic Modeling For Transporter Induction and Suppr...mentioning

confidence: 99%

Regulation of Drug Transport Proteins—From Mechanisms to Clinical Impact: A White Paper on Behalf of the International Transporter Consortium

Brouwer

Evers

Hayden

et al. 2022

Clin Pharma and Therapeutics

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Membrane transport proteins are involved in the absorption, disposition, efficacy, and/or toxicity of many drugs. Numerous mechanisms (e.g., nuclear receptors, epigenetic gene regulation, microRNAs, alternative splicing, post-translational modifications, and trafficking) regulate transport protein levels, localization, and function. Various factors associated with disease, medications, and dietary constituents, for example, may alter the regulation and activity of transport proteins in the intestine, liver, kidneys, brain, lungs, placenta, and other important sites, such as tumor tissue. This white paper reviews key mechanisms and regulatory factors that alter the function of clinically relevant transport proteins involved in drug disposition. Current considerations with in vitro and in vivo models that are used to investigate transporter regulation are discussed, including strengths, limitations, and the inherent challenges in predicting the impact of changes due to regulation of one transporter on compensatory pathways and overall drug disposition. In addition, translation and scaling of in vitro observations to in vivo outcomes are considered. The importance of incorporating altered transporter regulation in modeling and simulation approaches to predict the clinical impact on drug disposition is also discussed. Regulation of transporters is highly complex and, therefore, identification of knowledge gaps will aid in directing future research to expand our understanding of clinically relevant molecular mechanisms of transporter regulation. This information is critical to the development of tools and approaches to improve therapeutic outcomes by predicting more accurately the impact of regulation-mediated changes in transporter function on drug disposition and response.Transport proteins of the solute carrier (SLC) and ATP-binding cassette (ABC) superfamilies are widely recognized as key determinants of the absorption, distribution, and excretion of many endogenous compounds and xenobiotics, including drugs, bile acids, hormones, and nutrients, which may thereby directly or indirectly impact medication efficacy and/or safety. Not surprisingly, intersubject variability in drug response due to transporters has been attributed to altered transporter function in organs, such as the intestine, liver, and kidneys. 1,2 Mechanisms of alterations in drug transporter activity have focused primarily on (i) differences in gene expression and/ or protein abundance due to genetic polymorphisms; and (ii) drug-drug interactions (DDIs) predominantly involving direct

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Section: Pharmacokinetic Modeling For Transporter Induction and Suppr...mentioning

confidence: 99%

Regulation of Drug Transport Proteins—From Mechanisms to Clinical Impact: A White Paper on Behalf of the International Transporter Consortium

Brouwer

Evers

Hayden

et al. 2022

Clin Pharma and Therapeutics

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“…The more sensitive NR assay indicated that among drugs alone the most effective in cell killing was paclitaxel with the IC 50 equal to 50.35, 55.56, and 2.53 nM for A549, U118 MG, and HaCaT cells, respectively (Figure 5). (mainly clathrin-mediated endocytosis) [74,75] and the processes of regurgitation by P-glycoprotein, which are present in the tested cell lines [72,76]. The possibility of penetration of the studied nanoparticles by clathrin-mediated endocytosis is confirmed by the fact that it concerns nanoparticles with a diameter of approx.…”

Section: Cytotoxicitymentioning

confidence: 70%

“…In this study, we have used a glycidylated dendrimer, which was supposed to reduce the uptake of conjugates by HaCaT cells, compared to the tumor cells [53]. Differences in the degree of absorption of individual conjugates are difficult to explain, as they may be related to ER-mediated endocytosis [73] or EGFR-mediated endocytosis (mainly clathrin-mediated endocytosis) [74,75] and the processes of regurgitation by P-glycoprotein, which are present in the tested cell lines [72,76]. The possibility of penetration of the studied nanoparticles by clathrin-mediated endocytosis is confirmed by the fact that it concerns nanoparticles with a diameter of approx.…”

Section: Cellular Accumulationmentioning

confidence: 99%

Exploring the Potential of Lapatinib, Fulvestrant, and Paclitaxel Conjugated with Glycidylated PAMAM G4 Dendrimers for Cancer and Parasite Treatment

Uram,

Wróbel,

Walczak

et al. 2023

Molecules

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Fulvestrant (F), lapatinib (L), and paclitaxel (P) are hydrophobic, anticancer drugs used in the treatment of estrogen receptor (ER) and epidermal growth factor receptor (EGFR)-positive breast cancer. In this study, glycidylated PAMAM G4 dendrimers, substituted with F, L, and/or P and targeting tumor cells, were synthesized and characterized, and their antitumor activity against glioma U-118 MG and non-small cell lung cancer A549 cells was tested comparatively with human non-tumorogenic keratinocytes (HaCaT). All cell lines were ER+ and EGFR+. In addition, the described drugs were tested in the context of antinematode therapy on C. elegans. The results show that the water-soluble conjugates of G4P, G4F, G4L, and G4PFL actively entered the tested cells via endocytosis due to the positive zeta potential (between 13.57–40.29 mV) and the nanoparticle diameter of 99–138 nm. The conjugates of G4P and G4PFL at nanomolar concentrations were the most active, and the least active conjugate was G4F. The tested conjugates inhibited the proliferation of HaCaT and A549 cells; in glioma cells, cytotoxicity was associated mainly with cell damage (mitochondria and membrane transport). The toxicity of the conjugates was proportional to the number of drug residues attached, with the exception of G4L; its action was two- and eight-fold stronger against glioma and keratinocytes, respectively, than the equivalent of lapatinib alone. Unfortunately, non-cancer HaCaT cells were the most sensitive to the tested constructs, which forced a change in the approach to the use of ER and EGFR receptors as a goal in cancer therapy. In vivo studies on C. elegans have shown that all compounds, most notably G4PFL, may be potentially useful in anthelmintic therapy.

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“…If the observed ABCB1 changes seen in this study are in fact accompanied by changes in the P-gp expression without any reduction in P-gp activity, this could potentially affect embryonic development in numerous ways. Among others, P-gp is important in cortisol regulation 41 and lipid transportation 32 . Alterations in cortisol supply to the fetus could hence influence fetal organ and especially brain maturation 42,43 , an organ believed to be sensitive towards maternal obesity 10,14,15 .…”

Section: Discussionmentioning

confidence: 99%

ABCB1 expression is increased in human first trimester placenta from pregnant women classified as overweight or obese

Justesen

Bilde

Olesen

et al. 2023

Sci Rep

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Obesity has become a global health challenge also affecting reproductive health. In pregnant women, obesity increases the risk of complications such as preterm birth, macrosomia, gestational diabetes, and preeclampsia. Moreover, obesity is associated with long-term adverse effects for the offspring, including increased risk of cardiovascular and metabolic diseases and neurodevelopmental difficulties. The underlying mechanisms are far from understood, but placental function is essential for pregnancy outcome. Transporter proteins P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) are important for trans-placental transport of endogenous substances like lipids and cortisol, a key hormone in tissue maturation. They also hold a protective function protecting the fetus from xenobiotics (e.g. pharmaceuticals). Animal studies suggest that maternal nutritional status can affect expression of placental transporters, but little is known about the effect on the human placenta, especially in early pregnancy. Here, we investigated if overweight and obesity in pregnant women altered mRNA expression of ABCB1 encoding P-gp or ABCG2 encoding BCRP in first trimester human placenta. With informed consent, 75 first trimester placental samples were obtained from women voluntarily seeking surgical abortion (< gestational week 12) (approval no.: 20060063). Villous samples (average gestational age 9.35 weeks) were used for qPCR analysis. For a subset (n = 38), additional villi were snap-frozen for protein analysis. Maternal BMI was defined at the time of termination of pregnancy. Compared to women with BMI 18.5–24.9 kg/m2 (n = 34), ABCB1 mRNA expression was significantly increased in placenta samples from women classified as overweight (BMI 25–29.9 kg/m2, n = 18) (p = 0.040) and women classified as obese (BMI ≥ 30 kg/m2, n = 23) (p = 0.003). Albeit P-gp expression did not show statistically significant difference between groups, the effect of increasing BMI was the same in male and female pregnancies. To investigate if the P-gp increase was compensated, we determined the expression of ABCG2 which was unaffected by maternal obesity (p = 0.291). Maternal BMI affects ABCB1 but not ABCG2 mRNA expression in first trimester human placenta. Further studies of early placental function are needed to understand how the expression of placental transport proteins is regulated by maternal factors such as nutritional status and determine the potential consequences for placental–fetal interaction.

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Suppression of P-glycoprotein by cigarette smoke extract in human lung-derived A549/P-gp cells

Cited by 4 publications

References 25 publications

Regulation of Drug Transport Proteins—From Mechanisms to Clinical Impact: A White Paper on Behalf of the International Transporter Consortium

Regulation of Drug Transport Proteins—From Mechanisms to Clinical Impact: A White Paper on Behalf of the International Transporter Consortium

Exploring the Potential of Lapatinib, Fulvestrant, and Paclitaxel Conjugated with Glycidylated PAMAM G4 Dendrimers for Cancer and Parasite Treatment

ABCB1 expression is increased in human first trimester placenta from pregnant women classified as overweight or obese

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