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The Involvement of Pregnane X Receptor-regulated Pathways in the Antitumor Activity of Cisplatin

Megumi Yasuda1, Shuichi Kishimoto2, Manabu Amano1

  • 1Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe, Japan.

Anticancer Research
|July 3, 2019
PubMed
Abstract

Insights

Nuclear receptors, like pregnane X receptor (PXR), influence cisplatin resistance. PXR antagonists show promise in overcoming this resistance by enhancing chemotherapy

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Cancer Research

Background:

  • Nuclear receptors regulate cellular transporters, potentially contributing to cisplatin (CDDP) resistance.
  • Understanding these mechanisms is crucial for developing strategies to overcome treatment failure.

Purpose of the Study:

  • To investigate if nuclear receptor ligands can be used as drugs to overcome CDDP resistance.
  • To explore the role of pregnane X receptor (PXR) in CDDP resistance.

Main Methods:

  • Caspase-3 activity was measured using fluorogenic substrates.
  • mRNA levels were quantified via real-time polymerase chain reaction (PCR).

Main Results:

  • Pregnane X receptor (PXR) expression changed with CDDP-induced caspase-3 activation in HepG2 cells.
  • Rifampicin (PXR agonist) decreased CDDP accumulation and inhibited growth and caspase-3 activation.
  • Leflunomide (PXR antagonist) significantly enhanced CDDP-induced caspase-3 activation in HepG2 and CDDP-resistant HepG2/R cells.

Conclusions:

  • PXR modulates CDDP's antitumor activity, likely by regulating transporter-mediated intracellular CDDP concentration.
  • PXR antagonists represent a potential therapeutic strategy for overcoming CDDP resistance.
Keywords:
Cisplatinapoptosispregnane X receptortransporter

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