Psorospermin structural requirements for P-glycoprotein resistance reversal

Steven S. Carey, Mary Gleason-Guzman, Vijay Gokhale, Laurence Hurley

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3617-3623
Number of pages7
JournalMolecular Cancer Therapeutics
Volume7
Issue number11
DOIs
StatePublished - Nov 1 2008

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P-Glycoprotein
Multiple Myeloma
Doxorubicin
psorospermin
Drug Therapy
Type II DNA Topoisomerase
Alkylating Agents
Biological Products
Drug Resistance
Flow Cytometry
Western Blotting
Cell Line
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Psorospermin structural requirements for P-glycoprotein resistance reversal. / Carey, Steven S.; Gleason-Guzman, Mary; Gokhale, Vijay; Hurley, Laurence.

In: Molecular Cancer Therapeutics, Vol. 7, No. 11, 01.11.2008, p. 3617-3623.

Research output: Contribution to journalArticle

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