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Differential cell responses to nanoparticle docetaxel and small molecule docetaxel at a sub-therapeutic dose range.

ABSTRACT: Current preclinical evaluations of nanoparticle taxanes have focused on the effect of nanoparticle size and shape on the efficacy and toxicity. It is generally assumed that nanoparticle therapeutics have the same cellular response on tumor and normal cells as their small molecule counterparts. Here, we show that nanoparticle taxanes can mediate cellular effects distinct from that of small molecule taxanes at the sub-therapeutic dose range. Cells that are exposed to two polymeric nanoparticle formulations of docetaxel were found to undergo a different cell cycle and cell fate than those of cells that were exposed to small molecule docetaxel. Our results suggest that nanoparticle formulation of therapeutics can affect the therapeutic effect of its cargo.

From the clinical editor

This study investigates the differences between subtherapeutic doses of docetaxel applied as small molecules vs. nanoparticle formulations, demonstrating differential effects on the cell cycle and overall cell fate. The study suggests that the carrier may change the therapeutic effects of its cargo, which has important implications on future research.

SUBMITTER: Wang EC

PROVIDER: S-EPMC3912219 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Differential cell responses to nanoparticle docetaxel and small molecule docetaxel at a sub-therapeutic dose range.

Wang Edina C EC Sinnott Rebecca R Werner Michael E ME Sethi Manish M Whitehurst Angelique W AW Wang Andrew Z AZ

Nanomedicine : nanotechnology, biology, and medicine 20130803 2

Current preclinical evaluations of nanoparticle taxanes have focused on the effect of nanoparticle size and shape on the efficacy and toxicity. It is generally assumed that nanoparticle therapeutics have the same cellular response on tumor and normal cells as their small molecule counterparts. Here, we show that nanoparticle taxanes can mediate cellular effects distinct from that of small molecule taxanes at the sub-therapeutic dose range. Cells that are exposed to two polymeric nanoparticle for ...[more]

PMID: 23916886

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Project description:BackgroundThe mechanism of small-molecule stabilised protein-protein interactions is of growing interest in the pharmacological discovery process. A plethora of different substances including the aromatic sulphonamide E7820 have been identified to act by such a mechanism. The process of E7820 induced CAPERα degradation and the resultant transcriptional down regulation of integrin α2 expression has previously been described for a variety of different cell lines and been made responsible for E7820's antiangiogenic activity. Currently the application of E7820 in the treatment of various malignancies including pancreas carcinoma and breast cancer is being investigated in pre-clinical and clinical trials. It has been shown, that integrin α2 deficiency has beneficial effects on bone homeostasis in mice. To transfer E7820 treatment to bone-related pathologies, as non-healing fractures, osteoporosis and bone cancer might therefore be beneficial. However, at present no data is available on the effect of E7820 on osseous cells or skeletal malignancies.MethodsPre-osteoblastic (MC3T3 and Saos-2) cells and endothelial (eEnd2 cells and HUVECs) cells, each of human and murine origin respectively, were investigated. Vitality assay with different concentrations of E7820 were performed. All consecutive experiments were done at a final concentration of 50 ng/ml E7820. The expression and production of integrin α2 and CAPERα were investigated by quantitative real-time PCR and western blotting. Expression of CAPERα splice forms was differentiated by semi-quantitiative reverse transcriptase PCR.ResultsHere we present the first data showing that E7820 can increase integrin α2 expression in the pre-osteoblast MC3T3 cell line whilst also reproducing canonical E7820 activity in HUVECs. We show that the aberrant activity of E7820 in MC3T3 cells is likely due to differential activity of CAPERα at the integrin α2 promoter, rather than due to differential CAPERα degradation or differential expression of CAPERα spliceforms.ConclusionThe results presented here indicate that E7820 may not be suitable to treat certain malignancies of musculoskeletal origin, due to the increase in integrin α2 expression it may induce. Further investigation of the differential functioning of CAPERα and the integrin α2 promoter in cells of various origin would however be necessary to more clearly differentiate between cell lines that will positively respond to E7820 from those that will not.

Dataset Information

Differential cell responses to nanoparticle docetaxel and small molecule docetaxel at a sub-therapeutic dose range.

From the clinical editor

Publications

Differential cell responses to nanoparticle docetaxel and small molecule docetaxel at a sub-therapeutic dose range.

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