Dynamic assessment of mitoxantrone resistance and modulation of multidrug resistance by valspodar (PSC833) in multidrug resistance human cancer cells

Fei Shen, Barbara J. Bailey, Shaoyou Chu, Aimee K. Bence, Xinjian Xue, Priscilla Erickson, Ahmad Safa, William T. Beck, Leonard C. Erickson

Research output: Contribution to journalArticle

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Abstract

P-glycoprotein (Pgp), a member of the ATP-binding cassette transporter family, is one of the major causes for multidrug resistance (MDR). We report using confocal microscopy to study the roles of Pgp in mediating the efflux of the anticancer agent mitoxantrone and the reversal of MDR by the specific Pgp inhibitor valspodar (PSC833). The net uptake and efflux of mitoxantrone and the effect of PSC833 were quantified and compared in Pgp-expressing human cancer MDA-MB-435 (MDR) cells and in parental wild-type cells. The MDR cells, transduced with the human Pgp-encoding gene MDR1 construct, were approximately 8-fold more resistant to mitoxantrone than the wild-type cells. Mitoxantrone accumulation in the MDR cells was 3-fold lower than that in the wild-type cells. The net uptake of mitoxantrone in the nuclei and cytoplasm of MDR cells was only 58 and 67% of that in the same intracellular compartment of the wild-type cells. Pretreatment with PSC833 increased the accumulation of mitoxantrone in the MDR cells to 85% of that in the wild-type cells. In living animals, the accumulation of mitoxantrone in MDA-MB-435mdr xenograft tumors was 61% of that in the wild-type tumors. Administration of PSC833 to animals before mitoxantrone treatment increased the accumulation of mitoxantrone in the MDR tumors to 94% of that in the wild-type tumors. These studies have added direct in vitro and in vivo visual information on how Pgp processes anticancer compounds and how Pgp inhibitors modulate MDR in resistant cancer cells.

Original languageEnglish
Pages (from-to)423-429
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume330
Issue number2
DOIs
StatePublished - Aug 2009

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Mitoxantrone
Multiple Drug Resistance
P-Glycoprotein
Neoplasms
valspodar
ATP-Binding Cassette Transporters
Heterografts
Confocal Microscopy
Antineoplastic Agents
Cytoplasm

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

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Dynamic assessment of mitoxantrone resistance and modulation of multidrug resistance by valspodar (PSC833) in multidrug resistance human cancer cells. / Shen, Fei; Bailey, Barbara J.; Chu, Shaoyou; Bence, Aimee K.; Xue, Xinjian; Erickson, Priscilla; Safa, Ahmad; Beck, William T.; Erickson, Leonard C.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 330, No. 2, 08.2009, p. 423-429.

Research output: Contribution to journalArticle

Shen, Fei ; Bailey, Barbara J. ; Chu, Shaoyou ; Bence, Aimee K. ; Xue, Xinjian ; Erickson, Priscilla ; Safa, Ahmad ; Beck, William T. ; Erickson, Leonard C. / Dynamic assessment of mitoxantrone resistance and modulation of multidrug resistance by valspodar (PSC833) in multidrug resistance human cancer cells. In: Journal of Pharmacology and Experimental Therapeutics. 2009 ; Vol. 330, No. 2. pp. 423-429.
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