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Down-regulation of catalase gene expression in the doxorubicin-resistant AML subline AML-2/DX100

H S Kim1, T B Lee, C H Choi

  • 1Department of Pharmacology, Chosun University Medical School, 375 Seosuk-dong, Dong-gu, Kwangju, 501-759, South Korea.

Biochemical and Biophysical Research Communications
|February 17, 2001
PubMed

Insights

Multidrug resistance (MDR) in cancer chemotherapy is a challenge. This study found that decreased catalase activity, not MRP overexpression, explains why some resistant AML cells are paradoxically sensitive to peroxides.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Multidrug resistance (MDR) is a significant hurdle in cancer chemotherapy, often involving the overexpression of drug efflux pumps like multidrug resistance-associated protein (MRP).
  • A doxorubicin-resistant acute myeloid leukemia (AML) subline (AML-2/DX100) overexpressed MRP but exhibited paradoxical sensitivity to reactive oxygen species (ROS) generating agents like peroxides and paraquat.

Purpose of the Study:

  • To investigate the underlying mechanisms behind the paradoxical sensitivity of MRP-overexpressing AML cells to ROS-generating agents.
  • To compare the activities of key antioxidant enzymes in drug-sensitive and resistant AML cell lines.

Main Methods:

  • Comparative analysis of antioxidant enzyme activities (superoxide dismutases, glutathione S-transferase, catalase, glutathione reductase, glutathione peroxidase, glucose-6-phosphate dehydrogenase) between AML-2/WT and AML-2/DX100 cells.
  • Gene expression analysis using Western blot and reverse transcription-polymerase chain reaction (RT-PCR) to confirm catalase down-regulation.
  • Assessment of catalase activity stability in the absence of doxorubicin and in the presence of an MRP inhibitor (probenecid).

Main Results:

  • Catalase activity was significantly reduced (to about one-third) in the MRP-overexpressing AML-2/DX100 cells compared to the drug-sensitive AML-2/WT cells.
  • This reduction in catalase activity was directly attributed to decreased catalase gene expression.
  • The diminished catalase activity was independent of MRP overexpression and persisted even after drug withdrawal or MRP inhibition.

Conclusions:

  • The paradoxical sensitivity of MRP-overexpressing AML cells to peroxides and paraquat is due to down-regulation of catalase gene expression.
  • This down-regulation of catalase is independent of MRP overexpression.
  • Reduced catalase activity represents a potential therapeutic vulnerability, or 'Achilles' heel,' in certain resistant cancer cells.

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