title: Stearoyl gemcitabine nanoparticles overcome resistance related to the over-expression of ribonucleotide reductase subunit M1.
abstract: 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.
authors.affiliation: The University of Texas at Austin, College of Pharmacy, Pharmaceutics Division, Austin, Texas 78712, USA.
authors.forename: Woon-Gye
authors.initials: WG
authors.lastname: Chung
authors.forename: Michael A
authors.initials: MA
authors.lastname: Sandoval
authors.forename: Brian R
authors.initials: BR
authors.lastname: Sloat
authors.forename: Dharmika S P
authors.initials: DS
authors.lastname: Lansakara-P
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Cui
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial / Q000187:drug effects* / Q000502:physiology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D011897:Random Allocation; D012262:Ribonucleoside Diphosphate Reductase; D013228:Stearates / Q000008:administration & dosage* / Q000737:chemistry; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis*; D000093542:Gemcitabine
chemical_list: D013228:Stearates; D025521:Tumor Suppressor Proteins; D003841:Deoxycytidine; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; D000093542:Gemcitabine