title: Anticancer efficacy of squalenoyl gemcitabine nanomedicine on 60 human tumor cell panel and on experimental tumor.
abstract: Gemcitabine (2',2'-difluorodeoxyribofuranosylcytosine) is an anticancer nucleoside analogue active against a wide variety of solid tumors. However, following intravenous administration, this drug is rapidly inactivated by enzymatic deamination and displays a short biological half-life necessitating the administration of high doses leading also to unwanted side effects. To overcome these drawbacks and to improve the therapeutic index of gemcitabine, we have recently developed the concept of squalenoylation which consisted in the bioconjugation of gemcitabine with squalene, a natural lipid. In our preliminary studies, we have shown that this bioconjugate (SQgem) self-organized in water as nanoassemblies with considerable resistance to deamination and significantly higher anticancer activity compared with gemcitabine in an intravenously grafted tumor model in mice. To further establish the candidature of this nanomedicine for clinical trials, in this communication we have tested the preclinical efficacy of squalenoyl gemcitabine nanomedicine on several human tumor cell lines and on the subcutaneously grafted experimental L1210 murine tumor in mice. SQgem nanomedicine displayed an efficient cytotoxicity against a variety of human tumor cell lines in the 60 human tumor cell panel. In vivo, following intravenous administration, SQgem nanomedicine displayed a superior anticancer activity against subcutaneous L1210 tumor, comparatively to gemcitabine. The molecular mechanism behind the anticancer efficacy of SQgem has been investigated by flow cytometry analysis and protein expression profiling of L1210 wt cells treated in vitro with the squalenoyl gemcitabine bioconjugate. It was found that this nanomedicine arrested the cell cycle in G2/M, characterized by an increased cyclin A and cyclin E expression, and activation of caspase-3 and the cleavage of poly(ADP-ribose) polymerase with an increase of cytochrome C level. Taken together, these results suggest that the cell kill by this nanomedicine occurred through mitochondrial apoptotic triggered pathway, similarly to that of gemcitabine free.
authors.affiliation: Universite Paris-Sud XI, Faculte de Pharmacie, UMR CNRS 8612, IFR 141, 92296 Chatenay-Malabry Cedex, France.
authors.forename: L Harivardhan
authors.initials: LH
authors.lastname: Reddy
authors.forename: Jack-Michel
authors.initials: JM
authors.lastname: Renoir
authors.forename: Veronique
authors.initials: V
authors.lastname: Marsaud
authors.forename: Sinda
authors.initials: S
authors.lastname: Lepetre-Mouelhi
authors.forename: Didier
authors.initials: D
authors.lastname: Desmaële
authors.forename: Patrick
authors.initials: P
authors.lastname: Couvreur
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D019925:Cyclin A / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D050997:Nanomedicine; D049329:Nanostructures / Q000737:chemistry*; D036103:Nanotechnology; D040081:Protein Array Analysis; D013185:Squalene / Q000031:analogs & derivatives / Q000737:chemistry; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D019925:Cyclin A; D019927:Cyclin E; D003841:Deoxycytidine; D013185:Squalene; D053148:Caspase 3; C019556:squalane; D000093542:Gemcitabine