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Updated: Jan 19, 2026
Cognitive Enhancers: Cholinesterase Inhibitors and NMDA Receptor Antagonists
Comparison of Pregnane X Receptor Antagonists for Enhancing the Antitumor Effect of Cisplatin
Megumi Yasuda1, Shuichi Kishimoto2, Manabu Amano1
1Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe, Japan.
Background:
Cisplatin is a platinum compound capable of inducing apoptosis of cancer cells. However, cancer cells can become cisplatin-resistant. A recent study showed that a pregnane X receptor (PXR) antagonist, leflunomide, can enhance the antitumor activity of cisplatin and overcome such resistance. This study determined whether PXR antagonists ketoconazole and phenethyl isothiocyanate (PEITC) enhance the antitumor activity of platinum compounds and by which mechanism(s) of action.
Materials And Methods:
Caspase-3 activity, intracellular platinum level, and expression of ATP-binding cassette subfamily C member 2 (ABCC2; previously named multidrug resistance-associated protein 2) were assessed in HepG2 human hepatocellular carcinoma cells exposed to carboplatin or cisplatin with and without PXR antagonist.
Results:
In combination with platinum compounds, PEITC increased the intracellular platinum level, while ketoconazole induced higher caspase-3 activity. Additionally, PEITC suppressed ABCC2 protein expression.
Conclusion:
These results suggested that ketoconazole and PEITC enhance the antitumor activity of platinum compounds by different and complex mechanisms.
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