Related Experiment Video

Updated: Jun 20, 2026

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
08:49

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

Published on: January 22, 2019

PSC833, cyclosporine analogue, downregulates MDR1 expression by activating JNK/c-Jun/AP-1 and suppressing NF-kappaB

H Bark1, Cheol-Hee Choi

  • 1Department of Pharmacology, Research Center for Resistant Cells, Chosun University Medical School, 375 Seosuk-dong Dong-gu, Gwangju, 501-759, Korea.

Cancer Chemotherapy and Pharmacology
|September 19, 2009
PubMed
Abstract

Insights

PSC833 enhances doxorubicin efficacy by increasing drug accumulation and downregulating multidrug resistance (MDR) gene expression. This occurs through activating the JNK/c-Jun/AP-1 pathway and suppressing NF-kappaB signaling in lung cancer cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Multidrug resistance (MDR) is a significant barrier to effective cancer chemotherapy.
  • P-glycoprotein (Pgp), encoded by the MDR1 gene, is a key mediator of MDR.
  • PSC833 is a known inhibitor of Pgp function.

Purpose of the Study:

  • To investigate if PSC833 alters MDR1 gene expression.
  • To identify the mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-kappaB) pathways involved in PSC833's effects on MDR1 expression.

Main Methods:

  • Cytotoxicity assessed by MTT assay.
  • Intracellular drug accumulation analyzed via flow cytometry.
  • Gene and protein expression studied using RT-PCR and Western blot.
  • Transcription factor DNA-binding activity determined by electrophoretic mobility shift assays.

Main Results:

  • PSC833 sensitized doxorubicin-resistant lung cancer cells (SK-MES-1/DX1000) to doxorubicin.
  • PSC833 reduced intracellular accumulation of Pgp substrates.
  • PSC833 dose- and time-dependently downregulated MDR1 mRNA and Pgp expression.
  • PSC833 activated JNK/c-Jun/AP-1 signaling and suppressed NF-kappaB nuclear translocation.

Conclusions:

  • PSC833 enhances doxorubicin sensitivity by increasing drug accumulation.
  • PSC833 downregulates MDR1 expression via JNK/c-Jun/AP-1 activation and NF-kappaB suppression.
  • These findings highlight PSC833's dual role in overcoming MDR.

More Related Videos

Mechanism of Kemeng Fang's Inhibition of Podocyte Apoptosis in Rats with Membranous Nephropathy through the PI3K/AKT Signaling Pathway07:15

Mechanism of Kemeng Fang's Inhibition of Podocyte Apoptosis in Rats with Membranous Nephropathy through the PI3K/AKT Signaling Pathway

Published on: August 23, 2024

Related Concept Videos

Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR activation may...
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
NF-κB-dependent Signaling Pathway02:26

NF-κB-dependent Signaling Pathway

The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Inhibition of CDK Activity02:34

Inhibition of CDK Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...