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Comparative cellular pharmacology of daunorubicin and idarubicin in human multidrug-resistant leukemia cells
Abstract:
We examined the effect of daunorubicin (DNR), the new anthracycline derivative idarubicin (IDR), and verapamil on two leukemia cell lines that displayed the multidrug resistant (MDR) phenotype and used laser flow cytometry to quantitate intracellular anthracycline content. The vinblastine-resistant human lymphoblastic leukemia cell line CEM-VBL demonstrated minimal DNR uptake; simultaneous incubation with verapamil and DNR increased intracellular DNR uptake fourfold. IDR uptake was 10 times more rapid in these cells and simultaneous incubation with IDR and verapamil resulted in only a 1.2-fold increase of intracellular IDR. Similar results were observed in the vincristine-resistant human myeloid leukemia cell line HL-60/RV+. Intracellular retention of DNR and IDR was also measured in each cell line. In CEM-BVL cells, 38% of the original DNR concentration remained after a 2-hour resuspension in fresh medium compared with 71% of the original IDR concentration. In HL-60/RV+ cells, 36% of the DNR concentration remained compared with 51% of the IDR concentration. After incubation of CEM-VBL and HL-60/RV+ cells with DNR for 1 hour followed by resuspension in fresh medium plus verapamil, intracellular DNA retention increased 5- and 5.2-fold, respectively. However, incubation of these cells for 1 hour with IDR followed by resuspension in fresh medium plus verapamil resulted in only a 1.6- and 2.4-fold increase in intracellular IDR retention. Lastly, clonogenic experiments were performed to correlate intracellular anthracycline content with cytotoxicity. DNR alone had a minimal effect on the clonogenic growth of CEM-VBL cells, whereas the combination of DNR plus verapamil resulted in approximately 80% growth inhibition. However, incubation of these cells with IDR alone resulted in greater than 95% growth inhibition. These results suggest that IDR may be more effective than DNR in leukemia cells that display the MDR phenotype.
Insights
Idarubicin (IDR) shows greater efficacy than daunorubicin (DNR) in multidrug-resistant (MDR) leukemia cells. Verapamil enhances DNR uptake but has minimal effect on IDR, suggesting IDR is a promising agent for MDR leukemia treatment.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Multidrug resistance (MDR) is a major challenge in leukemia treatment.
- Anthracyclines like daunorubicin (DNR) are standard chemotherapy agents.
- Verapamil is known to reverse MDR in some cancer cells.
Purpose of the Study:
- To compare the efficacy of daunorubicin (DNR) and idarubicin (IDR) in MDR leukemia cell lines.
- To investigate the effect of verapamil on the intracellular uptake and retention of DNR and IDR.
- To correlate intracellular anthracycline content with cytotoxicity in MDR leukemia cells.
Main Methods:
- Utilized two human leukemia cell lines with MDR phenotype (CEM-VBL and HL-60/RV+).
- Employed laser flow cytometry to quantify intracellular DNR and IDR content.
- Performed clonogenic assays to assess cytotoxicity.
Main Results:
- IDR exhibited significantly higher and faster intracellular uptake compared to DNR in MDR cells.
- Verapamil markedly increased intracellular DNR levels but had a limited effect on IDR.
- IDR alone demonstrated superior cytotoxicity (>95% growth inhibition) compared to DNR plus verapamil (approx. 80% inhibition) in MDR leukemia cells.
Conclusions:
- Idarubicin (IDR) may be more effective than daunorubicin (DNR) in treating leukemia with the multidrug-resistant (MDR) phenotype.
- Verapamil enhances DNR's effectiveness but is less impactful with IDR.
- IDR warrants further investigation as a potential therapeutic agent for MDR leukemia.