Alteration of Genomic Responses to Doxorubicin and Prevention of MDR in Breast Cancer Cells by a Polymer Excipient:  Pluronic P85

Abstract

Polymer therapeutics has emerged as a new clinical option for the treatment of human diseases. However, little is known about pharmacogenetic responses to drugs formulated with polymers. In this study, we demonstrate that a formulation containing the block copolymer Pluronic P85 and antineoplastic drug, doxorubicin (Dox), prevents the development of multidrug resistance in the human breast carcinoma cell line, MCF7. Specifically, MCF7 cells cultured in the presence of Pluronic were unable to stably grow in concentrations of Dox that exceeded 10ng Dox/ml of culture media. In sharp contrast, MCF7 cells cultured in the absence of the block copolymer resulted in the selection and stable growth of cells that tolerated 1000 times higher concentration of the drug (10,000ng Dox/ml culture media). Detailed characterization of the isolated sublines demonstrated that those cells selected in the polymer-drug formulation did not show amplification of the MDR1 gene, likely resulting in their high sensitivity to the drug. Conversely, cells selected with Dox alone showed an elevated level in the expression of the MDR1 gene along with a corresponding increase in the expression level of the drug efflux transporter, Pgp, and likely contributing to the high resistance of the cells to Dox. Global analysis of the expression profiles of 20K genes by DNA microarray revealed that the use of Pluronic in combination with Dox drastically changed the direction and magnitude of the genetic response of the tumor cells to Dox and may potentially enhance therapeutic outcomes. Overall, this study reinforces the need for a thorough assessment of pharmacogenomic effects of polymer therapeutics.

Doxorubicin activates FOXO3a to induce the expression of multidrug resistance gene ABCB1 (MDR1) in K562 leukemic cells

“…ABCB1 confers drug resistance by increasing the ability of cells to pump out hydrophobic cytotoxic drugs, such as doxorubicin (28). Thus, although induction of FOXO3a in response to anticancer drug treatment may cause cell cycle arrest and apoptosis (32), prolonged FOXO3a activation and increased ABCB1 expression may be critical to the development of acquired MDR.…”

Motility-related actinin alpha-4 is associated with advanced and metastatic ovarian carcinoma

“…18,19 All DNA microarray gene expression studies used human oligonucleotide arrays custom printed by a dedicated core facility within the Eppley Institute for Research in Cancer and Allied Diseases (University of Nebraska Medical Center, Omaha, NE, USA) as described previously. 18,19 Arrays were constructed from a set of 12 140 sense oligonucleotide (60-mers) probes designed for each human target gene by Compugen Inc. (Rockville, MD, USA) and manufactured by Sigma-Genosys Inc. (The Woodlands, TX, USA). Individual arrays contain 12 288 spot features, including 12 107 different genes, 28 replications of GAPDH and negative controls.…”

Nanotechnology to Combat Multidrug Resistance in Cancer

“…Their fi ndings revealed that there was a threefold decrease in IC50 value by DOXO-loaded sPEL/CD as compared to free DOXO in resistant MCF-7/ADR cells. They concluded that the mPEG-PLA block segment of sPEL/CD complex was having identical activities as pluronic in averting MDR in cancer cells owing to their contrasting structural resemblance [ 88 ]. Moreover, it was presumed that alteration of the normal functioning of P-gp by polymers might also be a probable mechanism of the reversal of MDR by sPEL/CD.…”