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 IC(50) values compared to parental cells, but these values were much less than IC(50) 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.