Adriamycin Resistance in Human Tumor Cells Associated with Marked Alterations in the Regulation of the Hexose Monophosphate Shunt and Its Response to Oxidant Stress

Grace Chao Yeh, Sandra J. Occhipinti, Kenneth H Cowan, Bruce A. Chabner, Charles E. Myers

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Abstract

We found that Adriamycin increased the pentose phosphate shunt activity in both Adriamycin-sensitive (WT) and Adriamycin-resistant (ADRR) human breast cancer MCF-7 cells. In contrast, hydrogen peroxide and cumene hydroperoxide markedly stimulated pentose-shunt activity in ADRR but only moderately increased the activity in WT cells. Furthermore, the altered oxidation-reduction regulation is associated with changes intrinsic to the key enzymes of the pentose-shunt pathway, glucose-6-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase and with glutathione peroxidase. We found the Vmax values for glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase were 50- and 4-fold lower, respectively, in ADRR than WT cells and the Kma of NADP4 were 10-fold lower in ADRR than WT. The activity of glutathione reductase in ADRR is 42% of that in WT. In spite of these changes, the response of the cells to both hydrogen peroxide and organic peroxide is not limited by either the capacity of the pentose shunt or glutathione reductase, but is determined by the activity of glutathione peroxidase and a glutathione transferase which possess peroxidase activity. The kinetic properties of the glucose-6-phosphate dehydrogenase in ADRR may, however, seriously limit the activity of cytochrome P-450 reductase, a major enzyme of Adriamydn conversion to a free radical.

Original languageEnglish (US)
Pages (from-to)5994-5999
Number of pages6
JournalCancer Research
Volume47
Issue number22
StatePublished - Jan 1 1987

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Pentose Phosphate Pathway
Oxidants
Doxorubicin
Glucosephosphate Dehydrogenase
Neoplasms
Phosphogluconate Dehydrogenase
Glutathione Reductase
Glutathione Peroxidase
Hydrogen Peroxide
NADPH-Ferrihemoprotein Reductase
MCF-7 Cells
Peroxides
Enzymes
Glutathione Transferase
Peroxidase
Oxidation-Reduction
Free Radicals
Breast Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Adriamycin Resistance in Human Tumor Cells Associated with Marked Alterations in the Regulation of the Hexose Monophosphate Shunt and Its Response to Oxidant Stress. / Yeh, Grace Chao; Occhipinti, Sandra J.; Cowan, Kenneth H; Chabner, Bruce A.; Myers, Charles E.

In: Cancer Research, Vol. 47, No. 22, 01.01.1987, p. 5994-5999.

Research output: Contribution to journalArticle

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AB - We found that Adriamycin increased the pentose phosphate shunt activity in both Adriamycin-sensitive (WT) and Adriamycin-resistant (ADRR) human breast cancer MCF-7 cells. In contrast, hydrogen peroxide and cumene hydroperoxide markedly stimulated pentose-shunt activity in ADRR but only moderately increased the activity in WT cells. Furthermore, the altered oxidation-reduction regulation is associated with changes intrinsic to the key enzymes of the pentose-shunt pathway, glucose-6-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase and with glutathione peroxidase. We found the Vmax values for glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase were 50- and 4-fold lower, respectively, in ADRR than WT cells and the Kma of NADP4 were 10-fold lower in ADRR than WT. The activity of glutathione reductase in ADRR is 42% of that in WT. In spite of these changes, the response of the cells to both hydrogen peroxide and organic peroxide is not limited by either the capacity of the pentose shunt or glutathione reductase, but is determined by the activity of glutathione peroxidase and a glutathione transferase which possess peroxidase activity. The kinetic properties of the glucose-6-phosphate dehydrogenase in ADRR may, however, seriously limit the activity of cytochrome P-450 reductase, a major enzyme of Adriamydn conversion to a free radical.

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