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)
Over-expression of
P-glycoprotein
(
P-gp
), an ATP-dependent drug efflux pump, represents one of the major mechanisms that contribute to multidrug resistance (MDR) in cancer cells. This study examined the effects of troglitazone, a ligand of peroxisome proliferator-activated receptor gamma (PPARgamma), on
P-gp
-mediated MDR in SGC7901/VCR cells (a vincristine-resistant human gastric cancer cell line). The expression of
P-gp
was detected by RT-PCR and Western blotting, respectively. The SGC7901/VCR cells were treated with 0.1 mg/L vincristine (VCR) alone or in combination with 1, 5, 10 micromol/L troglitazone for 24 h. PPARgamma was measured by electrophoretic mobility shift assay (EMSA). The intracellular concentration of Rhodamine123 (Rh123, a fluorescent
P-gp
substrate) was assayed to evaluate the activity of
P-gp
. The cell cycle and apoptosis were measured by flow cytometry. The results showed that the
P-gp
was increasingly expressed in SGC7901, BGC823 and SGC7901/VCR cells in turn, suggesting that MDR in the SGC7901/VCR cells was mediated by the increased expression of
P-gp
. In the SGC7901/VCR cells, the expression level of total PPARgamma was increased, however, the protein level and activity of PPARgamma in the nuclei of cells decreased significantly.
Troglitazone
elevated the PPARgamma activity in SGC7901/VCR cells in a dose-dependent manner.
Troglitazone
decreased the
P-gp
expression and markedly enhanced the accumulation of Rh123 in SGC7901/VCR cells in a dose-dependent manner. We also found that troglitazone significantly increased the percentage of SGC7901/VCR cells in the G2/M phase and decreased the cell percentage in G1 and S phase in a dose-dependent manner.
Troglitazone
significantly increased the apoptotic rate of SGC7901/VCR cells treated by VCR or ADR in a dose-dependent manner. It was concluded that
P-gp
-overexpressed SGC7901/VCR cells have minor endogenous PPARgamma activity. Elevation of the PPARgamma activity by troglitazone can reverse
P-gp
-mediated MDR via down-regulating the expression and activity of
P-gp
in SGC7901/VCR cells. It was suggested that troglitazone can dramatically enhance the sensitivity of
P-gp
-mediated MDR cancer cells to chemotherapeutic agents.
...
PMID:Reversal of P-glycoprotein-mediated multidrug resistance in SGC7901/VCR cells by PPARgamma activation by troglitazone. 2055 76
P-glycoprotein
(
P-gp
)-mediated multidrug resistance (MDR) in tumor cells is still a main obstacle for the chemotherapeutic treatment of cancers. Therefore, identification of safe and effective MDR reversing compounds with minimal adverse side effects is an important approach in the cancer treatment. Studies show that peroxisome proliferator-activated receptor (PPARs) ligands can inhibit cell growth in many cancers. Here, we investigated the effect of different PPAR agonists include fenofibrate, troglitazone and aleglitazar on doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells. The effects of doxorubicin (DOX) following treatment with PPAR agonists on cell viability were evaluated using MTT assay and the reversal fold (RF) values. Rhodamine123 (Rh123) assays were used to determine
P-gp
functioning.
P-gp
mRNA/protein expression was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot analysis after incubation with troglitazone and aleglitazar. Our results showed that troglitazone and aleglitazar significantly enhanced the cytotoxicity of DOX and decreased the RF values in K562/DOX cells, however, no such results were found for fenofibrate.
Troglitazone
and aleglitazar significantly down regulated
P-gp
expression in K562/DOX cells; in addition, the present study revealed that aleglitazar elevated intracellular accumulation of Rh123in K562/DOX cells as short-term effects, which also contribute to the reversal of MDR. These findings show that troglitazone and especially aleglitazar exhibited potent effects in the reversal of
P-gp
-mediated MDR, suggesting that these compounds may be effective for combination therapy strategies and circumventing MDR in K562/DOX cells to other conventional chemotherapeutic drugs.
...
PMID:Differential effects of peroxisome proliferator-activated receptor agonists on doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells. 2671 39
