Effects of Zuccagnia punctata extracts and their flavonoids on the function and expression of ABCB1/P-glycoprotein multidrug transporter

Chieli, Elisabetta; Romiti, Nadia; Zampini, Iris Catiana; Garrido, Gabino; Isla, Marı́a Inés

doi:10.1016/j.jep.2012.10.012

Cited by 24 publications

(11 citation statements)

References 24 publications

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“…These contradictory observations have been previously reported by other authors (Di Pietro et al, 2002; Deferme and Augustijns, 2003) and could be due to the different concentrations used in the experiments (Yuan et al, 2012), the type of cancer cells tested (Di Pietro et al, 2002) and differences in the interactions between the flavonoids and P-gp depending on the substrate used in the experiments (Di Pietro et al, 2002; Eid et al, 2015). On the other hand, the chalcone 6 was capable of potentiating DOX toxicity, not only by interfering with P-gp, as was previously determined (Chieli et al, 2012), but also and mainly, by some additional mechanism as deduced by the RF observed in K562 (Table 1). …”

Section: Discussionsupporting

confidence: 67%

Mechanism Underlying the Reversal of Drug Resistance in P-Glycoprotein-Expressing Leukemia Cells by Pinoresinol and the Study of a Derivative

et al. 2017

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P-glycoprotein (P-gp) is a membrane protein associated with multidrug resistance (MDR) due to its key role in mediating the traffic of chemotherapeutic drugs outside cancer cells, leading to a cellular response that hinders efforts toward successful therapy. With the aim of finding agents that circumvent the MDR phenotype mediated by P-gp, 15 compounds isolated from native and naturalized plants of Argentina were screened. Among these, the non-cytotoxic lignan (±) pinoresinol successfully restored sensitivity to doxorubicin from 7 μM in the P-gp overexpressed human myelogenous leukemia cells, Lucena 1. This resistance-reversing effect was confirmed by competitively increasing the intracellular doxorubicin accumulation and by significantly inhibiting the efflux of doxorubicin and, to a lesser extent, that of rhodamine 123. The activity obtained was similar to that observed with verapamil. No such results were observed in the sensitive parental K562 cell line. To gain deeper insight into the mode of action of pinoresinol, its effect on P-gp function and expression was examined. The docking simulations indicated that the lignan bound to P-gp at the apex of the V-shaped transmembrane cavity, involving transmembrane helices 4, 5, and 6, and partially overlapped the binding region of tariquidar, which was used as a positive control. These results would shed some light on the nature of its interaction with P-gp at molecular level and merit further mechanistic and kinetic studies. In addition, it showed a maximum 29% activation of ATP hydrolysis and antagonized verapamil-stimulated ATPase activity with an IC50 of 20.9 μM. On the other hand, pinoresinol decreased the presence of P-gp in the cell surface. Derivatives of pinoresinol with improved activity were identified by docking studies. The most promising one, the non-cytotoxic 1-acetoxypinoresinol, caused a reversion of doxorubicin resistance from 0.11 μM and thus higher activity than the lead compound. It also caused a significant increase in doxorubicin accumulation. Results were similar to those observed with verapamil. The results obtained positioned these compounds as potential candidates for effective agents to overcome P-gp-mediated MDR, leading to better outcomes for leukemia chemotherapy.

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Section: Discussionsupporting

confidence: 67%

Mechanism Underlying the Reversal of Drug Resistance in P-Glycoprotein-Expressing Leukemia Cells by Pinoresinol and the Study of a Derivative

et al. 2017

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“…It was reported that verapamil can increase the accumulation of Rh-123 in Caco-2 cells or MDCK-MDR1 (Chieli et al. 2012 ; Hu et al. 2016 ; Miao et al.…”

Section: Discussionmentioning

confidence: 99%

Chrysosplenetin inhibits artemisinin efflux in P-gp-over-expressing Caco-2 cells and reverses P-gp/MDR1 mRNA up-regulated expression induced by artemisinin in mouse small intestine

Wei

Yang

et al. 2016

Pharmaceutical Biology

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Context: CYP3A4 and P-gp together form a highly efficient barrier for orally absorbed drugs and always share the same substrates. Our previous work revealed that chrysosplenetin (CHR) significantly augmented the rat plasma level and anti-malarial efficacy of artemisinin (ART), partially due to the uncompetitive inhibition effect of CHR on rat CYP3A. But the impact of CHR on P-gp is still unknown.Objective: The present study investigates whether CHR interferes with P-gp-mediated efflux of ART and elucidates the underlying mechanism.Materials and methods: P-gp-over-expressing Caco-2 cells were treated with ART (10 μM) or ART-CHR (1:2, 10:20 μM) in ART bidirectional transport experiment. ART concentration was determined by UHPLC-MS/MS method. Healthy male ICR mice were randomly divided into nine groups (n = 6) including negative control (0.5% CMC-Na solution, 13 mL/kg), ART alone (40 mg/kg), verapamil (positive control, 40 mg/kg), ART-verapamil (1:1, 40:40 mg/kg), CHR alone (80 mg/kg), ART-CHR (1:0.1, 40:4 mg/kg), ART-CHR (1:1, 40:40 mg/kg), ART-CHR (1:2, 40:80 mg/kg) and ART-CHR (1:4, 40:160 mg/kg). The drugs were administrated intragastrically for seven consecutive days. MDR1 and P-gp expression levels in mice small intestine were examined by performing RT-PCR and western blot analysis. ABC coupling ATPase activity was also determined.Results: After combined with CHR (1:2), Papp (AP-BL) and Papp (BL-AP) of ART changed to 4.29 × 10 − 8 (increased 1.79-fold) and 2.85 × 10 − 8 cm/s (decreased 1.24-fold) from 2.40 × 10 − 8 and 3.54 × 10 − 8 cm/s, respectively. Efflux ratio (PBA/PAB) declined 2.21-fold (p < 0.01) versus to ART alone. ART significantly up-regulated both MDR1 mRNA and P-gp levels compared with vehicle, while CHR in combination ratio of 0:1, 0.1:1, 1:1, 2:1 and 4:1 with ART, reversed them to normal levels as well as negative control (p < 0.05). The ATPase activities in ART-CHR 1:4 and CHR alone groups achieved a slight increase (p < 0.05) when compared with ART alone.Discussion and conclusion: These results confirm that CHR inhibited P-gp activity and reverse the up-regulated P-gp and MDR1 levels induced by ART. It suggested that CHR potentially can be used as a P-gp reversal agent to obstruct ART multidrug resistance.

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“…Other important activities of Z. punctata extract and its flavonoids have been reported, such as modulation of expression and activity of the best known membrane efflux pump, ABCB1 P-glycoprotein multidrug transporter, involved in drug resistance (Chieli et al 2012) and cytoprotective effect on ethanol-induced gastroduodenal tract injuries in rats (de la Rocha et al 2003). In addition, no acute toxicity of the hydroalcoholic extract and 2´,4´-dihydroxychalcone isolated from it has been determined in the in vitro comet assay test on human hepatoma HepG2 cells (Zampini et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Effect of structurally related flavonoids from Zuccagnia punctata Cav. on Caenorhabditis elegans

D’Almeida

Arena

Morgan

et al. 2014

Acta Parasitologica

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Zuccagnia punctata Cav. (Fabaceae), commonly called jarilla macho or pus-pus, is being used in traditional medicine as an antiseptic, anti-inflammatory and to relieve muscle and bone pain. The aim of this work was to study the anthelmintic effects of three structurally related flavonoids present in aerial parts of Z. punctata Cav. The biological activity of the flavonoids 7-hydroxyflavanone (HF), 3,7-dihydroxyflavone (DHF) and 2´,4´-dihydroxychalcone (DHC) was examined in the free-living nematode Caenorhabditis elegans. Our results showed that among the assayed flavonoids, only DHC showed an anthelmintic effect and alteration of egg hatching and larval development processes in C. elegans. DHC was able to kill 50% of adult nematodes at a concentration of 17 μg/mL. The effect on larval development was observed after 48 h in the presence of 25 and 50 μg/mL DHC, where 33.4 and 73.4% of nematodes remained in the L3 stage or younger. New therapeutic drugs with good efficacy against drug-resistant nematodes are urgently needed. Therefore, DHC, a natural compound present in Z. punctata, is proposed as a potential anthelmintic drug.

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Effects of Zuccagnia punctata extracts and their flavonoids on the function and expression of ABCB1/P-glycoprotein multidrug transporter

Cited by 24 publications

References 24 publications

Mechanism Underlying the Reversal of Drug Resistance in P-Glycoprotein-Expressing Leukemia Cells by Pinoresinol and the Study of a Derivative

Mechanism Underlying the Reversal of Drug Resistance in P-Glycoprotein-Expressing Leukemia Cells by Pinoresinol and the Study of a Derivative

Chrysosplenetin inhibits artemisinin efflux in P-gp-over-expressing Caco-2 cells and reverses P-gp/MDR1 mRNA up-regulated expression induced by artemisinin in mouse small intestine

Effect of structurally related flavonoids from Zuccagnia punctata Cav. on Caenorhabditis elegans

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