Document Detail

Stearoyl gemcitabine nanoparticles overcome resistance related to the over-expression of ribonucleotide reductase subunit M1.
MedLine Citation:
PMID:  21851843     Owner:  NLM     Status:  MEDLINE    
Gemcitabine is a deoxycytidine analog used in the treatment of various solid tumors. However, tumors often develop resistances over time, which becomes a major issue for most gemcitabine-related chemotherapies. In the present study, a previously reported stearoyl gemcitabine nanoparticle formulation (GemC18-NPs) was evaluated for its ability to overcome gemcitabine resistance. In the wild type CCRF-CEM human leukemia cells, the IC(50) value of GemC18-NPs was 9.5-fold greater than that of gemcitabine hydrochloride (HCl). However, in the CCRF-CEM-AraC-8C cells that are deficient in the human equilibrative nucleoside transporter-1, the IC(50) of GemC18-NPs was only 3.4-fold greater than that in the parent CCRF-CEM cells, whereas the IC(50) of gemcitabine HCl was 471-fold greater than that in the parent CCRF-CEM cells. The GemC18-NPs were also more cytotoxic than gemcitabine HCl in the deoxycytidine kinase deficient (CCRF-CEM/dCK(-/-)) tumor cells. Similar to gemcitabine HCl, GemC18-NPs induced apoptosis through caspase activation. Another gemcitabine-resistant tumor cell line, TC-1-GR, was developed in our laboratory. In the TC-1-GR cells, the IC(50) of GemC18-NPs was only 5% of that of gemcitabine HCl. Importantly, GemC18-NPs effectively controlled the growth of gemcitabine resistant TC-1-GR tumors in mice, whereas the molar equivalent dose of gemcitabine HCl did not show any activity against the growth of the TC-1-GR tumors. Proteomics analysis revealed that the TC-1-GR cells over-expressed ribonucleotide reductase M1, which was likely the cause of the acquired gemcitabine resistance in the TC-1-GR cells. To our best knowledge, this represents the first report demonstrating that a nanoparticle formulation of gemcitabine overcomes gemcitabine resistance related to ribonucleotide reductase M1 over-expression.
Woon-Gye Chung; Michael A Sandoval; Brian R Sloat; Dharmika S P Lansakara-P; Zhengrong Cui
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural     Date:  2011-08-07
Journal Detail:
Title:  Journal of controlled release : official journal of the Controlled Release Society     Volume:  157     ISSN:  1873-4995     ISO Abbreviation:  J Control Release     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2012-01-17     Completed Date:  2012-09-28     Revised Date:  2014-09-13    
Medline Journal Info:
Nlm Unique ID:  8607908     Medline TA:  J Control Release     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  132-40     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Elsevier B.V. All rights reserved.
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MeSH Terms
Cell Line, Tumor
Chemistry, Pharmaceutical
Deoxycytidine / administration & dosage,  analogs & derivatives*,  chemistry
Dose-Response Relationship, Drug
Drug Resistance, Bacterial / drug effects*,  physiology
Gene Expression Regulation, Enzymologic*
Mice, Nude
Nanoparticles / administration & dosage*,  chemistry
Random Allocation
Stearates / administration & dosage*,  chemistry
Tumor Suppressor Proteins / biosynthesis*
Grant Support
CA135274/CA/NCI NIH HHS; R01 CA135274/CA/NCI NIH HHS; R01 CA135274-01A1/CA/NCI NIH HHS; R01 CA135274-02/CA/NCI NIH HHS; R01 CA135274-02S1/CA/NCI NIH HHS; R01 CA135274-03/CA/NCI NIH HHS; R01 CA135274-03S1/CA/NCI NIH HHS; R01 CA135274-04/CA/NCI NIH HHS; R01 CA135274-05/CA/NCI NIH HHS
Reg. No./Substance:
0/RRM1 protein, human; 0/Stearates; 0/Tumor Suppressor Proteins; 0W860991D6/Deoxycytidine; B76N6SBZ8R/gemcitabine
Comment In:
Nanomedicine (Lond). 2011 Nov;6(9):1491-2   [PMID:  22077460 ]

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