Reversal of multidrug resistance in cancer cells by pyranocoumarins isolated from Radix Peucedani

Jimmy Yiu Cheong Wu, David W F FONG*, Jin Xia Zhang, Chung Hang Leung, Hoi Lung Kwong, Meng Su Yang, Ding Li, Hon Yeung Cheung

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

179 Citations (Scopus)

Abstract

The pyranocoumarins, (±)-3′-angeloyl-4′-acetoxy-cis-khellactone, were isolated from Radix Peucedani, the dry root of Peucedanum praeruptorum Dunn, through bioassay-guided fractionation. The chemical structure of pyranocoumarins was determined by mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. X-ray crystallography showed that there are eight molecules (i.e. two each of four conformers) in each unit cell with their optical activities equally cancelled out. The four conformers are 3′(R)-angeloyl-4′(R)-acetoxy-khellactone in two conformational forms, and 3′(S)-angeloyl-4′(S)-acetoxy-khellactone in two conformational forms. Pyranocoumarins caused apoptotic cell death with IC50 of 41.9±2.8 and 17.3±8.2 μM for drug-sensitive KB-3-1 and multidrug resistant (MDR) KB-V1, respectively. The two- to threefold sensitivity difference between the two cell lines is interesting considering that the same ratio for doxorubicin is 50-300. Strong synergistic interactions were demonstrated when pyranocoumarins were combined with common anti-tumor drugs including doxorubicin, paclitaxel, puromycin or vincristine in MDR KB-V1 cell line, but not in drug-sensitive KB-3-1 cells. Pyranocoumarins increased doxorubicin accumulation in KB-V1 cells by about 25% after 6 h of incubation. Pyranocoumarins treatment for 24 h down-regulated the expression of P-glycoprotein in KB-V1 cells at both protein and mRNA levels. Pyranocoumarins also transiently reduced the cellular ATP contents in KB-V1 cells in a dose-dependent manner. Our results suggest that pyranocoumarins could be a potential MDR reversing agent.

Original languageEnglish
Pages (from-to)9-17
Number of pages9
JournalEuropean Journal of Pharmacology
Volume473
Issue number1
DOIs
Publication statusPublished - 18 Jul 2003

Scopus Subject Areas

  • Pharmacology

User-Defined Keywords

  • Apoptosis
  • KB-V1
  • Multidrug resistance
  • P-glycoprotein
  • Peucedanum praeruptorum Dunn
  • Pyranocoumarins

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