(±)-3′-O, 4′-O-dicynnamoyl-cis-khellactone, a derivative of (±)-praeruptorin A, reverses P-glycoprotein mediated multidrug resistance in cancer cells

Xiaoling Shen, Guangying Chen, Guoyuan Zhu, David W F Fong*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

51 Citations (Scopus)

Abstract

P-glycoprotein (Pgp) is an ATP-driven membrane exporter for a broad spectrum of hydrophobic xenobiotics. Pgp-overexpression is a common cause of multidrug resistance (MDR) in cancer cells and could lead to chemotherapeutic failure. Through an extensive herbal drug screening program we previously showed that (±)-praeruptorin A (PA), a naturally existing pyranocumarin isolated from the dried root of Peucedanum praeruptorum Dunn., re-sensitizes Pgp-mediated MDR (Pgp-MDR) cancer cells to cancer drugs. A number of PA derivatives were synthesized and one of these, (±)-3′-O, 4′-O-dicynnamoyl-cis-khellactone (DCK), was more potent than PA or verapamil in the reversal of Pgp-MDR. In Pgp-MDR cells DCK increased cellular accumulation of doxorubicin without affecting the expression level of Pgp. In Pgp-enriched membrane fractions DCK moderately stimulated basal Pgp-ATPase activity, suggesting some transport substrate-like function. However, DCK also inhibited Pgp-ATPase activity stimulated by the standard substrates verapamil or progesterone with decreased Vmaxs but Kms were relatively unchanged, suggesting a primarily non-competitive mode of inhibition. While the binding of substrates to active Pgp would increase the reactivity of the Pgp-specific antibody UIC2, DCK decreased UIC2 reactivity. These results suggest that DCK could bind simultaneously with substrates to Pgp but perhaps at an allosteric site and thus affect Pgp-substrate interactions.

Original languageEnglish
Pages (from-to)7138-7145
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume14
Issue number21
DOIs
Publication statusPublished - 1 Nov 2006

Scopus Subject Areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

User-Defined Keywords

  • (±)-3′-O, 4′-O-dicynnamoyl-cis-khellactone
  • (±)-Praeruptorin A
  • Multidrug resistance
  • P-glycoprotein

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