Prevention of MDR development in leukemia cells by micelle-forming polymeric surfactant

Amit K. Sharma, Li Zhang, Shu Li, David Lee Kelly, Valery Yu Alakhov, Elena V. Batrakova, Alexander V. Kabanov

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Doxorubicin (Dox) incorporated in nanosized polymeric micelles, SP1049C, has shown promise as monotherapy in patients with advanced esophageal carcinoma. The formulation contains amphiphilic block copolymers, Pluronics, that exhibit the unique ability to chemosensitize multidrug resistant (MDR) tumors by inhibiting P-glycoprotein (Pgp) drug efflux system and enhancing pro-apoptotic signaling in cancer cells. This work evaluates whether a representative block copolymer, Pluronic P85 (P85) can also prevent development of Dox-induced MDR in leukemia cells. For in vitro studies murine lymphocytic leukemia cells (P388) were exposed to increasing concentrations of Dox with/without P85. For in vivo studies, BDF1 mice bearing P388 ascite were treated with Dox or Dox/P85. The selected P388 cell sublines and ascitic tumor-derived cells were characterized for Pgp expression and functional activity (RT-PCR, Western Blot, rhodamine 123 accumulation) as well as Dox resistance (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay). The global gene expression was determined by oligonucleotide gene microarrays. We demonstrated that P85 prevented development of MDR1 phenotype in leukemia cells in vitro and in vivo as determined by Pgp expression and functional assays of the selected cells. Cells selected with Dox in the presence of P85 in vitro and in vivo exhibited some increases in IC50 values compared to parental cells, but these values were much less than IC50 in respective cells selected with the drug alone. In addition to mdr1, P85 abolished alterations of genes implicated in apoptosis, drug metabolism, stress response, molecular transport and tumorigenesis. In conclusion, Pluronic formulation can prevent development of MDR in leukemia cells in vitro and in vivo.

Original languageEnglish (US)
Pages (from-to)220-227
Number of pages8
JournalJournal of Controlled Release
Volume131
Issue number3
DOIs
StatePublished - Nov 12 2008

Fingerprint

Micelles
Surface-Active Agents
Leukemia
Doxorubicin
P-Glycoprotein
Poloxamer
Inhibitory Concentration 50
Pharmaceutical Preparations
Leukemia P388
Rhodamine 123
Lymphoid Leukemia
Neoplasms
Oligonucleotide Array Sequence Analysis
Ascites
Genes
Carcinogenesis
Western Blotting
Apoptosis
Carcinoma
Phenotype

Keywords

  • Doxorubicin
  • Multidrug resistance
  • P-glycoprotein
  • Pluronic
  • Poloxamer

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Prevention of MDR development in leukemia cells by micelle-forming polymeric surfactant. / Sharma, Amit K.; Zhang, Li; Li, Shu; Kelly, David Lee; Alakhov, Valery Yu; Batrakova, Elena V.; Kabanov, Alexander V.

In: Journal of Controlled Release, Vol. 131, No. 3, 12.11.2008, p. 220-227.

Research output: Contribution to journalArticle

Sharma, Amit K. ; Zhang, Li ; Li, Shu ; Kelly, David Lee ; Alakhov, Valery Yu ; Batrakova, Elena V. ; Kabanov, Alexander V. / Prevention of MDR development in leukemia cells by micelle-forming polymeric surfactant. In: Journal of Controlled Release. 2008 ; Vol. 131, No. 3. pp. 220-227.
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AU - Sharma, Amit K.

AU - Zhang, Li

AU - Li, Shu

AU - Kelly, David Lee

AU - Alakhov, Valery Yu

AU - Batrakova, Elena V.

AU - Kabanov, Alexander V.

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N2 - Doxorubicin (Dox) incorporated in nanosized polymeric micelles, SP1049C, has shown promise as monotherapy in patients with advanced esophageal carcinoma. The formulation contains amphiphilic block copolymers, Pluronics, that exhibit the unique ability to chemosensitize multidrug resistant (MDR) tumors by inhibiting P-glycoprotein (Pgp) drug efflux system and enhancing pro-apoptotic signaling in cancer cells. This work evaluates whether a representative block copolymer, Pluronic P85 (P85) can also prevent development of Dox-induced MDR in leukemia cells. For in vitro studies murine lymphocytic leukemia cells (P388) were exposed to increasing concentrations of Dox with/without P85. For in vivo studies, BDF1 mice bearing P388 ascite were treated with Dox or Dox/P85. The selected P388 cell sublines and ascitic tumor-derived cells were characterized for Pgp expression and functional activity (RT-PCR, Western Blot, rhodamine 123 accumulation) as well as Dox resistance (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay). The global gene expression was determined by oligonucleotide gene microarrays. We demonstrated that P85 prevented development of MDR1 phenotype in leukemia cells in vitro and in vivo as determined by Pgp expression and functional assays of the selected cells. Cells selected with Dox in the presence of P85 in vitro and in vivo exhibited some increases in IC50 values compared to parental cells, but these values were much less than IC50 in respective cells selected with the drug alone. In addition to mdr1, P85 abolished alterations of genes implicated in apoptosis, drug metabolism, stress response, molecular transport and tumorigenesis. In conclusion, Pluronic formulation can prevent development of MDR in leukemia cells in vitro and in vivo.

AB - Doxorubicin (Dox) incorporated in nanosized polymeric micelles, SP1049C, has shown promise as monotherapy in patients with advanced esophageal carcinoma. The formulation contains amphiphilic block copolymers, Pluronics, that exhibit the unique ability to chemosensitize multidrug resistant (MDR) tumors by inhibiting P-glycoprotein (Pgp) drug efflux system and enhancing pro-apoptotic signaling in cancer cells. This work evaluates whether a representative block copolymer, Pluronic P85 (P85) can also prevent development of Dox-induced MDR in leukemia cells. For in vitro studies murine lymphocytic leukemia cells (P388) were exposed to increasing concentrations of Dox with/without P85. For in vivo studies, BDF1 mice bearing P388 ascite were treated with Dox or Dox/P85. The selected P388 cell sublines and ascitic tumor-derived cells were characterized for Pgp expression and functional activity (RT-PCR, Western Blot, rhodamine 123 accumulation) as well as Dox resistance (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay). The global gene expression was determined by oligonucleotide gene microarrays. We demonstrated that P85 prevented development of MDR1 phenotype in leukemia cells in vitro and in vivo as determined by Pgp expression and functional assays of the selected cells. Cells selected with Dox in the presence of P85 in vitro and in vivo exhibited some increases in IC50 values compared to parental cells, but these values were much less than IC50 in respective cells selected with the drug alone. In addition to mdr1, P85 abolished alterations of genes implicated in apoptosis, drug metabolism, stress response, molecular transport and tumorigenesis. In conclusion, Pluronic formulation can prevent development of MDR in leukemia cells in vitro and in vivo.

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