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

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 V(max)s but K(m)s 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.

• Authors: Xiaoling Shen, Guangying Chen, Guoyuan Zhu, Wang-Fun Fong
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 14 Issue 21 Pg. 7138-45 (Nov 01 2006) ISSN: 0968-0896 [Print] England
• PMID: 16875827 (Publication Type: Journal Article)

Chemical References

• 3'-O, 4'-O-dicynnamoyl-cis-khellactone
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Coumarins
• praeruptorin A
• Doxorubicin
• Adenosine Triphosphatases

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (physiology)
• Adenosine Triphosphatases (metabolism)
• Antineoplastic Agents (pharmacology)
• Blotting, Western
• Cell Division (drug effects)
• Cell Line, Tumor
• Coumarins (chemistry, pharmacology)
• Doxorubicin (pharmacology)
• Drug Resistance, Multiple (physiology)
• Drug Resistance, Neoplasm (physiology)
• Drug Synergism
• Enzyme Activation
• G2 Phase (drug effects)
• Humans
• Substrate Specificity