Psorospermin structural requirements for P-glycoprotein resistance reversal.

Abstract

Resistance to chemotherapy reduces its effectiveness, resulting in increased mortality. Psorospermin, a natural product, is a topoisomerase II-directed DNA alkylating agent active against multidrug-resistant (MDR) cell lines, including multiple myeloma. In this study, the mechanism of the P-glycoprotein (P-gp) modulation activity of psorospermin and that of its associated pharmacophore were examined. Flow cytometry shows that doxorubicin-resistant multiple myeloma cells (8226/D40) pretreated with psorospermin enhance intracellular retention of doxorubicin compared with control (75% versus 38%). Because the overexpression of P-gp is the primary cause of drug resistance in the 8226/D40 cells, psorospermin-induced sensitization was likely due to mdr1/P-gp expressional or functional inhibition. As shown by PCR and Western blot, neither transcription of mdr1 nor translation of P-gp was down-regulated by psorospermin treatment. Therefore, the mechanism of psorospermin-induced resistance reversal is most likely through a direct interaction between psorospermin and P-gp. Furthermore, because only the (2'R,3'R) isomer of psorospermin showed any resistance reversal activity, the side chain of psorospermin is apparently a crucial moiety for resistance reversal. By understanding the mechanism of psorospermin-induced MDR modulation, psorospermin and similar compounds can be combined with other chemotherapies to treat resistant cancers.

• Authors: Steven S Carey, Mary Gleason-Guzman, Vijay Gokhale, Laurence H Hurley
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 7 Issue 11 Pg. 3617-23 (Nov 2008) ISSN: 1535-7163 [Print] United States
• PMID: 19001443 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents, Alkylating
• Xanthones
• psorospermin
• Doxorubicin

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Antineoplastic Agents, Alkylating (chemistry, pharmacology)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Doxorubicin (pharmacology)
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Humans
• Multiple Myeloma (drug therapy, metabolism)
• Transcription, Genetic
• Xanthones (chemistry, pharmacology)