Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.6.3.44 (
P-glycoprotein
)
13,344
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Human multidrug efflux transporters are known for their ability to extrude antibiotics and toxic compounds out of cells, yet accumulating data indicate they have additional functions in diverse physiological processes not related to drug efflux. Here, we show that the human multidrug transporter
P-glycoprotein
(
P-gp
) (also named MDR1 and ABCB1) is transcriptionally induced in the monocytic cell line
THP
-1 upon infection with the human intracellular bacterial pathogen Listeria monocytogenes. Notably, we found that
P-gp
is important for full activation of the type I interferon response elicited against L. monocytogenes bacteria. Both inhibition of
P-gp
function by verapamil and inhibition of its transcription using mRNA silencing led to a reduction in the magnitude of the type I response in infected cells. This function of
P-gp
was specific to type I interferon cytokines elicited against cytosolic replicating bacteria and was not observed in response to cyclic di-AMP (c-di-AMP), a molecule that was shown to be secreted by L. monocytogenes during infection and to trigger type I interferons. Moreover,
P-gp
was not involved in activation of other proinflammatory cytokines, such as those triggered by vacuolar-restricted L. monocytogenes or lipopolysaccharide (LPS). Taken together, these findings demonstrate a role for
P-gp
in proper development of an innate immune response against intracellular pathogens, highlighting the complexity in employing therapeutic strategies that involve inhibition of multidrug resistance (MDR) efflux pumps.
...
PMID:The human P-glycoprotein transporter enhances the type I interferon response to Listeria monocytogenes infection. 2582 30
Tumor cells can acquire multidrug resistance (MDR) as a result of drug efflux mediated by
P-glycoprotein
(
P-gp
). Here we report a targeted delivery system to carry pirarubicin (
THP
) to MDR breast cancer both in vitro and in vivo. PEG-derivatized vitamin E (PAMV
6
) amphiphiles loaded with
THP
were self-assembled in a single step. The PAMV
6
micelles showed unimodal size distribution and high drug loading efficiency. Cytotoxicity of PAMV
6
/
THP
was higher than that of free
THP
on MCF-7/ADR cells but comparable to that of
THP
on MCF-7 cells. PAMV
6
/
THP
was able to reverse MDR more than free
THP
in MCF-7/ADR cells, likely reflecting the remarkably higher intracellular
THP
concentration in micelle-treated cells and PAMV
6
-mediated inhibition of
P-gp
activity. PAMV
6
/
THP
micelles were internalized into MCF-7/ADR cells via macropinocytosis and caveolin-mediated endocytosis, further avoiding
P-gp
-mediated efflux. Mechanistic studies revealed that blank PAMV
6
micelles inhibited
P-gp
activity but did not affect
P-gp
expression, by significantly reducing mitochondrial membrane potential and slightly decreasing intracellular ATP levels. In a nude mouse xenograft model, PAMV
6
/
THP
led to much greater
THP
accumulation in tumors and much slower tumor growth than free
THP
. At the same time, PAMV
6
/
THP
was associated with significantly less severe bone marrow suppression and organ toxicity than free
THP
. Our results indicate that this PAMV
6
-based micelle system holds promise for combating MDR in cancer therapy.
...
PMID:One-Step Self-Assembling Nanomicelles for Pirarubicin Delivery To Overcome Multidrug Resistance in Breast Cancer. 2774 4
The effect of benznidazole (BZL) on the expression and activity of
P-glycoprotein
(P-gp, ABCB1) and multidrug resistance-associated protein 2 (MRP2, ABCC2), the two major transporters of endogenous and exogenous compounds, was evaluated in differentiated
THP
-1 cells. BZL induced P-gp and MRP2 proteins in a concentration-dependent manner. The increase in mRNA levels of both transporters suggests transcriptional regulation. P-gp and MRP2 activities correlated with increased protein levels. BZL intracellular accumulation was significantly lower in BZL-pre-treated cells than in control cells. PSC833 (a P-gp inhibitor) increased the intracellular BZL concentration in both pre-treated and control cells, confirming P-gp participation in BZL efflux.
...
PMID:Up-regulation of ATP-binding cassette transporters in the THP-1 human macrophage cell line by the antichagasic benznidazole. 2778 18
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