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Research ArticleExperimental Studies

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

MEGUMI YASUDA, SHUICHI KISHIMOTO, MANABU AMANO and SHOJI FUKUSHIMA
Anticancer Research July 2019, 39 (7) 3601-3608; DOI: https://doi.org/10.21873/anticanres.13507
MEGUMI YASUDA
1Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe, Japan
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SHUICHI KISHIMOTO
2Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan
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  • For correspondence: skisimot@pharm.kobegakuin.ac.jp
MANABU AMANO
1Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe, Japan
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SHOJI FUKUSHIMA
2Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan
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Abstract

Background/Aim: Nuclear receptors regulate the expression of cellular transporters, which may be contributing factors for cisplatin (CDDP) resistance. This study aimed to clarify whether nuclear receptor ligands could be potentially used as drugs to overcome CDDP resistance. Materials and Methods: Caspase-3 activity was measured using a fluorogenic substrate. mRNA levels were determined using real-time polymerase chain reaction. Results: Pregnane X receptor (PXR) showed an expression level change dependent on caspase-3 activation by CDDP in HepG2. Rifampicin, a PXR agonist, reduced the accumulation of CDDP and suppressed growth inhibition and caspase-3 activation in HepG2 after CDDP exposure. Leflunomide, a PXR antagonist, significantly enhanced caspase-3 activation by CDDP in HepG2 and CDDP-resistant HepG2/R. Conclusion: These results suggest that PXR can modify the antitumor activity of CDDP, presumably through regulating the expression of transporters, which control intracellular CDDP concentration. Thus, PXR antagonists can be further investigated as potential drugs capable of overcoming CDDP resistance.

  • Cisplatin
  • pregnane X receptor
  • transporter
  • apoptosis
  • Received April 26, 2019.
  • Revision received May 31, 2019.
  • Accepted June 3, 2019.
  • Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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Anticancer Research: 39 (7)
Anticancer Research
Vol. 39, Issue 7
July 2019
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The Involvement of Pregnane X Receptor-regulated Pathways in the Antitumor Activity of Cisplatin
MEGUMI YASUDA, SHUICHI KISHIMOTO, MANABU AMANO, SHOJI FUKUSHIMA
Anticancer Research Jul 2019, 39 (7) 3601-3608; DOI: 10.21873/anticanres.13507

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The Involvement of Pregnane X Receptor-regulated Pathways in the Antitumor Activity of Cisplatin
MEGUMI YASUDA, SHUICHI KISHIMOTO, MANABU AMANO, SHOJI FUKUSHIMA
Anticancer Research Jul 2019, 39 (7) 3601-3608; DOI: 10.21873/anticanres.13507
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Keywords

  • cisplatin
  • pregnane X receptor
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  • apoptosis
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