Decreased drug accumulation in a mitoxantrone-resistant gastric carcinoma cell line in the absence of P-glycoprotein

Udo Kellner, Lesley Hutchinson, André Seidel, Hermann Lage, Mary K. Danks, Manfred Dietel, Scott H. Kaufmann

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57 Scopus citations


An established gastric-carcinoma cell line, EPG85-257P, is extremely sensitive to mitoxantrone (IC50, 0.12 ng/ml). Stepwise selection with mitoxantrone for 3 years resulted in a cell line (EPG85-257RN) that is 7,056-fold resistant to mitoxantrone (IC50, 846 ng/ml) and displays cross-resistance to the topoisomerase(topo)-II poisons ametantrone (411x), etoposide(l 12x) and teniposide (60x) as well as the topo-I poisons 7-ethyl-10-hydroxycamptothecin (331x) and topotecan (58x). We now show that this resistance is multifactorial. Western blotting revealed a 5-fold decrease in topo-IIα polypeptide in the mitoxantrone-resistant cells. Immunohistochemistry and Western blotting failed to demonstrate F-glycoprotein overexpression. Formation of trapped topo-II-DNA complexes in the resistant cells required higher mitoxantrone concentrations than in parental cells, even though nuclei isolated from the EPG85-257RN cells formed cleavage complexes normally. In agreement with these observations, which suggest the possibility of a defect in mitoxantrone accumulation, examination of mitoxantrone accumulation in both cell lines by confocal laser microscopy revealed that the EPG85-257RN cells accumulate less mitoxantrone at steady state. From these results, we propose that mitoxantrone accumulation, along with alterations in topo-IIα expression, contribute to the resistance to mitoxantrone observed in these cells.

Original languageEnglish (US)
Pages (from-to)817-824
Number of pages8
JournalInternational Journal of Cancer
Issue number5
StatePublished - 1997

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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