Liposome-mediated modulation of multidrug resistance in human HL-60 leukemia cells

Aquilur Rahman, Syed R. Husain, Javed Siddiqui, Madhu Verma, Michael Agresti, Melvin Center, Ahmad Safa, Robert I. Glazer

Research output: Contribution to journalArticle

95 Citations (Scopus)

Abstract

Background: Multidrug resistance (MDR) is a major obstacle in cancer treatment. Resistance of cultured tumor cells to major classes of cytotoxic drugs is frequently due to expression of a plasma membrane P-glycoprotein encoded by MDR genes. We have demonstrated that liposome-encapsulated doxorubicin is more toxic than the free drug and that it modulates MDR in Chinese hamster LZ cells and human colon cancer cells. Purpose: To investigate further the association between expression of P-glycoprotein and modulation of MDR by liposome-encapsulated doxorubicin, we studied vincristine-resistant HL-60/VCR leukemia cells, which express P-glycoprotein, and doxorubicin-resistant HL-60/ADR leukemia cells, which do not. Methods: Cells were exposed to various concentrations of free doxorubicin and liposome-encapsulated doxorubicin. The cellular content of doxorubicin was determined by fluorescence analysis, and cytotoxicity was determined by cell growth inhibition. Photoaffinity-labeling studies of P-glycoprotein binding were performed on HL-60/VCR and HL-60/ ADR cells and KB-GSV2 cells transfected with the MDR1 gene (also known as PGY1). Results: The concentrations that caused 50% inhibition of growth (IC50) for free doxorubicin in HL-60, HL-60/ADR, and HL-60/VCR cells were 30 nM, 9 μM, and 0.9 μM, respectively. The values for liposome-encapsulated doxorubicin in parental HL-60 cells and HL-60/ADR cells were 20 nM and 9 μM, respectively, indicating little or no sensitization. In contrast, HL-60/ VCR cells were fivefold more sensitive to liposome-encapsulated doxorubicin than to free doxorubicin, and IC50 was reduced to 0.17 μM. In HL-60 cells exposed to liposome-encapsulated doxorubicin, intracellular doxorubicin accumulation was less than that seen with free drug. In contrast, in HL-60/VCR cells, accumulation was twofold to threefold higher than that with free doxorubicin. Liposome-encapsulated doxorubicin completely inhibited the photoaffinity labeling of P-glycoprotein by azidopine in membrane vesicles of HL-60/VCR cells, with a potency comparable to that of azidopine, suggesting that circumvention of MDR by liposomes is related to their specific interaction with P-glycoprotein. The studies with KB-GSV2 cells indicated that blank liposomes can directly inhibit photoaffinity labeling of P-glycoprotein. Conclusions: These results demonstrate the effectiveness of liposome-encapsulated doxorubicin in overcoming resistance in the multidrug-resistant phenotype of HL-60/ VCR cells by direct interaction with P-glycoprotein. Furthermore, they indicate that liposome-encapsulated doxorubicin may be an effective treatment for human cancers.

Original languageEnglish (US)
Pages (from-to)1909-1915
Number of pages7
JournalJournal of the National Cancer Institute
Volume84
Issue number24
StatePublished - Dec 16 1992
Externally publishedYes

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Liposomes
HL-60 Cells
Leukemia
Multiple Drug Resistance
Doxorubicin
Glycoproteins
Videocassette recorders
Modulation
Cell
P-Glycoprotein
Glycoprotein
Labeling
KB Cells
Resistance
Human
Genes
Cancer
Drugs
Cells
Inhibitory Concentration 50

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Physiology (medical)
  • Radiology Nuclear Medicine and imaging

Cite this

Rahman, A., Husain, S. R., Siddiqui, J., Verma, M., Agresti, M., Center, M., ... Glazer, R. I. (1992). Liposome-mediated modulation of multidrug resistance in human HL-60 leukemia cells. Journal of the National Cancer Institute, 84(24), 1909-1915.

Liposome-mediated modulation of multidrug resistance in human HL-60 leukemia cells. / Rahman, Aquilur; Husain, Syed R.; Siddiqui, Javed; Verma, Madhu; Agresti, Michael; Center, Melvin; Safa, Ahmad; Glazer, Robert I.

In: Journal of the National Cancer Institute, Vol. 84, No. 24, 16.12.1992, p. 1909-1915.

Research output: Contribution to journalArticle

Rahman, A, Husain, SR, Siddiqui, J, Verma, M, Agresti, M, Center, M, Safa, A & Glazer, RI 1992, 'Liposome-mediated modulation of multidrug resistance in human HL-60 leukemia cells', Journal of the National Cancer Institute, vol. 84, no. 24, pp. 1909-1915.
Rahman A, Husain SR, Siddiqui J, Verma M, Agresti M, Center M et al. Liposome-mediated modulation of multidrug resistance in human HL-60 leukemia cells. Journal of the National Cancer Institute. 1992 Dec 16;84(24):1909-1915.
Rahman, Aquilur ; Husain, Syed R. ; Siddiqui, Javed ; Verma, Madhu ; Agresti, Michael ; Center, Melvin ; Safa, Ahmad ; Glazer, Robert I. / Liposome-mediated modulation of multidrug resistance in human HL-60 leukemia cells. In: Journal of the National Cancer Institute. 1992 ; Vol. 84, No. 24. pp. 1909-1915.
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abstract = "Background: Multidrug resistance (MDR) is a major obstacle in cancer treatment. Resistance of cultured tumor cells to major classes of cytotoxic drugs is frequently due to expression of a plasma membrane P-glycoprotein encoded by MDR genes. We have demonstrated that liposome-encapsulated doxorubicin is more toxic than the free drug and that it modulates MDR in Chinese hamster LZ cells and human colon cancer cells. Purpose: To investigate further the association between expression of P-glycoprotein and modulation of MDR by liposome-encapsulated doxorubicin, we studied vincristine-resistant HL-60/VCR leukemia cells, which express P-glycoprotein, and doxorubicin-resistant HL-60/ADR leukemia cells, which do not. Methods: Cells were exposed to various concentrations of free doxorubicin and liposome-encapsulated doxorubicin. The cellular content of doxorubicin was determined by fluorescence analysis, and cytotoxicity was determined by cell growth inhibition. Photoaffinity-labeling studies of P-glycoprotein binding were performed on HL-60/VCR and HL-60/ ADR cells and KB-GSV2 cells transfected with the MDR1 gene (also known as PGY1). Results: The concentrations that caused 50{\%} inhibition of growth (IC50) for free doxorubicin in HL-60, HL-60/ADR, and HL-60/VCR cells were 30 nM, 9 μM, and 0.9 μM, respectively. The values for liposome-encapsulated doxorubicin in parental HL-60 cells and HL-60/ADR cells were 20 nM and 9 μM, respectively, indicating little or no sensitization. In contrast, HL-60/ VCR cells were fivefold more sensitive to liposome-encapsulated doxorubicin than to free doxorubicin, and IC50 was reduced to 0.17 μM. In HL-60 cells exposed to liposome-encapsulated doxorubicin, intracellular doxorubicin accumulation was less than that seen with free drug. In contrast, in HL-60/VCR cells, accumulation was twofold to threefold higher than that with free doxorubicin. Liposome-encapsulated doxorubicin completely inhibited the photoaffinity labeling of P-glycoprotein by azidopine in membrane vesicles of HL-60/VCR cells, with a potency comparable to that of azidopine, suggesting that circumvention of MDR by liposomes is related to their specific interaction with P-glycoprotein. The studies with KB-GSV2 cells indicated that blank liposomes can directly inhibit photoaffinity labeling of P-glycoprotein. Conclusions: These results demonstrate the effectiveness of liposome-encapsulated doxorubicin in overcoming resistance in the multidrug-resistant phenotype of HL-60/ VCR cells by direct interaction with P-glycoprotein. Furthermore, they indicate that liposome-encapsulated doxorubicin may be an effective treatment for human cancers.",
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AU - Rahman, Aquilur

AU - Husain, Syed R.

AU - Siddiqui, Javed

AU - Verma, Madhu

AU - Agresti, Michael

AU - Center, Melvin

AU - Safa, Ahmad

AU - Glazer, Robert I.

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N2 - Background: Multidrug resistance (MDR) is a major obstacle in cancer treatment. Resistance of cultured tumor cells to major classes of cytotoxic drugs is frequently due to expression of a plasma membrane P-glycoprotein encoded by MDR genes. We have demonstrated that liposome-encapsulated doxorubicin is more toxic than the free drug and that it modulates MDR in Chinese hamster LZ cells and human colon cancer cells. Purpose: To investigate further the association between expression of P-glycoprotein and modulation of MDR by liposome-encapsulated doxorubicin, we studied vincristine-resistant HL-60/VCR leukemia cells, which express P-glycoprotein, and doxorubicin-resistant HL-60/ADR leukemia cells, which do not. Methods: Cells were exposed to various concentrations of free doxorubicin and liposome-encapsulated doxorubicin. The cellular content of doxorubicin was determined by fluorescence analysis, and cytotoxicity was determined by cell growth inhibition. Photoaffinity-labeling studies of P-glycoprotein binding were performed on HL-60/VCR and HL-60/ ADR cells and KB-GSV2 cells transfected with the MDR1 gene (also known as PGY1). Results: The concentrations that caused 50% inhibition of growth (IC50) for free doxorubicin in HL-60, HL-60/ADR, and HL-60/VCR cells were 30 nM, 9 μM, and 0.9 μM, respectively. The values for liposome-encapsulated doxorubicin in parental HL-60 cells and HL-60/ADR cells were 20 nM and 9 μM, respectively, indicating little or no sensitization. In contrast, HL-60/ VCR cells were fivefold more sensitive to liposome-encapsulated doxorubicin than to free doxorubicin, and IC50 was reduced to 0.17 μM. In HL-60 cells exposed to liposome-encapsulated doxorubicin, intracellular doxorubicin accumulation was less than that seen with free drug. In contrast, in HL-60/VCR cells, accumulation was twofold to threefold higher than that with free doxorubicin. Liposome-encapsulated doxorubicin completely inhibited the photoaffinity labeling of P-glycoprotein by azidopine in membrane vesicles of HL-60/VCR cells, with a potency comparable to that of azidopine, suggesting that circumvention of MDR by liposomes is related to their specific interaction with P-glycoprotein. The studies with KB-GSV2 cells indicated that blank liposomes can directly inhibit photoaffinity labeling of P-glycoprotein. Conclusions: These results demonstrate the effectiveness of liposome-encapsulated doxorubicin in overcoming resistance in the multidrug-resistant phenotype of HL-60/ VCR cells by direct interaction with P-glycoprotein. Furthermore, they indicate that liposome-encapsulated doxorubicin may be an effective treatment for human cancers.

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