Dynamic Assessment of Mitoxantrone Resistance and Modulation of Multidrug Resistance by Valspodar (PSC833) in Multidrug Resistance Human Cancer Cells

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.

Vincristine-induced expression of P-glycoprotein in MOLM-13 and SKM-1 acute myeloid leukemia cell lines is associated with coexpression of nestin transcript

“…A typical feature of P-gp expression in leukemia cells is reduced sensitivity to a large group of structurally unrelated substances (reviewed in Breier et al 2005Breier et al , 2013a. Both resistant cell variants exert cross-resistance to doxorubicin and mitoxantrone (not shown), which have been shown to be P-gp substrates (Drobna et al 2002;Shen et al 2009). Vincristine could induce P-gp expression through activation of the pregnane X receptor (Huang et al 2006), which binds to the DR4 motif in the upstream enhancer region of the gene encoding P-gp and induces transcription (Geick et al 2001).…”

Reversion of Multidrug Resistance in a Chemoresistant Human Breast Cancer Cell Line by β-Elemene

“…cyclosporine [9], valspodar (PSC 833) [10], Pyronaridine [11], and natural and synthetic polymers [12]. Numerous plant-derived dietary compounds, for instance cnidiadin and schizandrins, could also modulate P-gp transport [13,14].…”

Eine strukturelle Evaluierung medizinalchemischer Strategien gegen Wirkstoffresistenzen

“…[113,123] Die Enantiomerentrennung von Verapamil (20)e rgab,d ass beide Enantiomere bezüglich des P-gp-Transporters die gleiche Aktivitäta ufweisen, allerdings wurde ein zehnfacher Unterschied hinsichtlich der Affinitätz um Calciumtransporter festgestellt, wobei das Dexverapamil (21,A bbildung 19) weniger aktiv ist. [125] Trotz dieser vielversprechenden Ergebnisse konnte in den klinischen Studien der Phase III mit Va lspodar und verschiedenen Chemotherapeutika keine signifikante Verbesserung festgestellt werden. [121] Der am intensivsten untersuchte P-gp-Inhibitor der zweiten Generation ist das cyclische Peptid Va lspodar (23), das von Sandoz/Novartis aus dem P-gp-Inhibitor der ersten Generation Cyclosporin entwickelt wurde (22,A bbildung 19).…”

“…Die Kombinationstherapie von Va lspodar mit dem Zytostatikum Mitoxantron in multiresistenten MDA-MB-435-Xenograft-Mäusetumoren zeigte einen Anstieg der Wirkstoffakkumulation von 61 %a uf 94 %. [125] Trotz dieser vielversprechenden Ergebnisse konnte in den klinischen Studien der Phase III mit Va lspodar und verschiedenen Chemotherapeutika keine signifikante Verbesserung festgestellt werden. Zusätzlich erlitten die mit Va lspodar behandelten Patienten stärkere toxische Nebenwirkungen.…”