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Characterization of daunorubicin resistance in K562 leukemia cells lacking daunorubicin reductase activity
1Department of Biochemical and Clinical Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee.
Abstract:
Daunorubicin (D1)-resistant cells have been isolated from daunorubicin reductase-deficient K562 cells, hence, metabolism of D1 to the alcohol metabolite daunorubicinol (D2) will not contribute to the development of resistance. The resistant cell lines were 22-123-fold resistant and were cross-resistant to a variety of drugs. Drug uptake and efflux were altered in the more resistant lines but not in the less resistant cells. Verapamil enhanced D1 cytotoxicity in all resistant lines; it inhibited D1 efflux in the higher resistant line thereby resulting in an increase in the cellular level of D1. However, this was not true for the less resistant line suggesting that verapamil enhancement of D1 toxicity in the less resistant line is probably due to other factors. Additionally, we have been unable to identify a marker glycoprotein in resistant cells. The changes observed in the resistant sublines are moderate and probably drug accumulation differences could not account for the degree of D1 resistance noted, nor could resistance be wholly reversed by calcium antagonist. Other factors may be involved in the development of resistance in these human cells.
Insights
Daunorubicin resistance in K562 cells is not due to metabolism. Verapamil enhances drug toxicity, but other factors likely contribute to daunorubicin resistance.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Daunorubicin (D1) is a chemotherapy drug.
- Drug resistance is a major challenge in cancer treatment.
- K562 cells are a human leukemia cell line.
Purpose of the Study:
- To investigate the mechanisms of daunorubicin resistance in K562 cells.
- To determine the role of drug metabolism and transport in resistance.
- To evaluate the effect of verapamil on daunorubicin cytotoxicity.
Main Methods:
- Isolation and characterization of daunorubicin-resistant K562 cell lines.
- Measurement of drug uptake and efflux.
- Assessment of drug cytotoxicity in the presence and absence of verapamil.
Main Results:
- Resistant cell lines showed 22-123-fold resistance to daunorubicin and cross-resistance to other drugs.
- Altered drug uptake and efflux were observed in highly resistant cells.
- Verapamil enhanced daunorubicin cytotoxicity in all resistant lines, inhibiting efflux in highly resistant cells.
Conclusions:
- Daunorubicin metabolism to daunorubicinol does not contribute to resistance in these cells.
- Drug accumulation differences may not fully explain the observed resistance.
- Other uncharacterized factors likely play a role in daunorubicin resistance development.