Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overexpression of the MDR1 gene is one of the reasons for multidrug resistance (MDR). Some studies suggested that antioxidants could down-regulate MDR1 expression as a possible cancer treatment. In this report, we try to determine the effects of antioxidants (catalase or N-acetylcysteine [NAC]) on the regulation of intrinsic MDR1 overexpression in HepG2 cells. Adding catalase or N-acetylcysteine to the HepG2 culture led to a significant increase of MDR1 mRNA and P-glycoprotein drug transporter activity. After catalase or NAC treatment, a reduced intracellular reactive oxygen species (ROS) was observed. The JNK inhibitor SP600125 abolished the positive effects of catalase on drug transporter activity in a dose-dependent manner. Furthermore, the up-regulation of P-glycoprotein functions by catalase was only observed in HepG2 cells but not in other cell lines tested (MCF-7, A549, A431). These data suggested that catalase can up-regulate P-glycoprotein expression in HepG2 cells via reducing intracellular ROS, and JNK may mediate this process.
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PMID:Up-regulation of P-glycoprotein expression by catalase via JNK activation in HepG2 cells. 1698 40

Salvicine, a novel diterpenoid quinone compound, displays potent antitumor activities in vitro and in vivo, which is under Phase II clinical trials for cancer therapy. Our previous studies have shown that salvicine effectively kills multidrug-resistant (MDR) cells and downregulates mdr-1 and P-glycoprotein (P-gp) levels by activation of transcription factor c-Jun in MDR K562/A02 cells. Recent studies have further demonstrated that salvicine-formed reactive oxygen species (ROS) contribute to its induction of cytotoxicity, DNA double strand breaks and apoptosis. In this study, we showed that salvicine induced equal ROS generation and glutathione depletion in both sensitive K562 and MDR K562/A02 cells. Pre-incubation with thiol antioxidants glutathione or N-acetyl-cysteine (NAC, precursor of intracellular glutathione) almost abolished the cytotoxicity of salvicine, which also could be attenuated by the H(2)O(2)-specific scavenger catalase. Moreover, NAC abrogated salvicine-induced DNA double strand breaks and apoptosis. Notably, both H(2)O(2) and vitamin C potentiated the cytotoxicity and apoptotic induction of salvicine in parental K562 and MDR K562/A02 cells, and catalase could remove such potentiation. Furthermore, pretreatment of K562/A02 cells with NAC eliminated P-gp downregulation, JNK phosphorylation and c-Jun activation induced by salvicine. Our data collectively indicate that salvicine-generated ROS contribute to both cell killing and P-gp downregulation in MDR K562/A02 cells, thus extending our prior related studies. This study also opens the possibility of the combination therapy of salvicine and vitamin C in the future.
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PMID:Reactive oxygen species contribute to cell killing and P-glycoprotein downregulation by salvicine in multidrug resistant K562/A02 cells. 1803 28

The aim of the present work was to compare the mucoadhesive and efflux pump P-glycoprotein (P-gp) interacting properties of chitosan (CS)- and glycolchitosan (GCS)-based thiomers and corresponding unmodified parent polymers. For this purpose, the glycol chitosan-N-acetyl-cysteine (GCS-NAC) and glycol chitosan-glutathione (GCS-GSH) thiomers were prepared under simple and mild conditions. Their mucoadhesive characteristics were studied by turbidimetric and zeta potential measurements. The P-gp interacting properties were evaluated measuring the effects of thiolated- and unmodified-polymers on the bidirectional transport (BA/AB) of rhodamine-123 across Caco-2 cells as well as in the calcein-AM and ATPase activity assays. Although all the thiomers and unmodified polymers showed optimal-excellent mucoadhesive properties, the best mucoadhesive performances have been obtained by CS and CS-based thiomers. Moreover, it was found that the pretreatment of Caco-2 cell monolayer with GCS-NAC or GCS restores Rho-123 cell entrance by inhibiting P-gp activity. Hence, GCS-NAC and GCS may constitute new biomaterials useful for improving the bioavailability of P-gp substrates.
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PMID:Mucoadhesive properties and interaction with P-glycoprotein (P-gp) of thiolated-chitosans and -glycol chitosans and corresponding parent polymers: a comparative study. 2452 Oct 85

Alantolactone (ALT), a sesquiterpene lactone component of Inula helenium, has been reported to exert anticancer activity in various cancers. However, the cellular targets and underlying mechanism of anticancer activity of ALT in various cancers including lung cancer has not been fully defined. In the present study, we found that ALT effectively inhibits proliferation and triggers oxidative stress mediated-apoptosis in A549 lung adenocarcinoma cells by inducing ER stress and mitochondrial dysfunction. This ALT-mediated apoptosis was inhibited by NAC while diamide potentiated it. Moreover, ALT effectively suppressed both constitutive and inducible STAT3 activation, inhibited its translocation into nucleus and decreased its DNA binding activity. Further mechanistic study revealed that ALT abrogated STAT3 activation by promoting STAT3 glutathionylation. ROS scavenger NAC reverted ALT-mediated STAT3 glutathionylation and inhibition of STAT3 phosphorylation. Finally, ALT enhanced chemosensitivity of A549 cells to doxorubicin and reversed doxorubicin resistance in A549/DR cells by inhibiting STAT3 activation and P-glycoprotein expression and increasing intracellular accumulation of doxorubicin. Suppression of STAT3 activation by targeting ROS metabolism with ALT thus discloses a previously unrecognized mechanism underlying the biological activity of ALT. Taken together; ALT induces oxidative stress-dependent apoptosis, inhibits STAT3 activation and augments doxorubicin toxicity in A549 lung cancer cells. These findings provide an in-depth insight into the molecular mechanism of ALT in the treatment of lung cancer.
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PMID:Alantolactone induces apoptosis, promotes STAT3 glutathionylation and enhances chemosensitivity of A549 lung adenocarcinoma cells to doxorubicin via oxidative stress. 2874 Jan 38