Protein expression profile of HT-29 human colon cancer cells after treatment with a cytotoxic daunorubicin-GnRH-III derivative bioconjugate.
Targeted delivery of chemotherapeutic agents is a new approach for the treatment of cancer, which provides increased selectivity and decreased systemic toxicity. We have recently developed a promising drug delivery system, in which the anticancer drug daunorubicin (Dau) was attached via oxime bond to a gonadotropin-releasing hormone-III (GnRH-III) derivative used as a targeting moiety (Glp-His-Trp-Lys(Ac)-His-Asp-Trp-Lys(Da  = Aoa)-Pro-Gly-NH2; Glp = pyroglutamic acid, Ac = acetyl; Aoa = aminooxyacetyl). This bioconjugate exerted in vitro cytostatic/cytotoxic effect on human breast, prostate and colon cancer cells, as well as significant in vivo tumor growth inhibitory effect on colon carcinoma bearing mice. In our previous studies, H-Lys(Dau = Aoa)-OH was identified as the smallest metabolite produced in the presence of rat liver lysosomal homogenate, which was able to bind to DNA in vitro. To get a deeper insight into the mechanism of action of the bioconjugate, changes in the protein expression profile of HT-29 human colon cancer cells after treatment with the bioconjugate or free daunorubicin were investigated by mass spectrometry-based proteomics. Our results indicate that several metabolism-related proteins, molecular chaperons and proteins involved in signaling are differently expressed after targeted chemotherapeutic treatment, leading to the conclusion that the bioconjugate exerts its cytotoxic action by interfering with multiple intracellular processes.
Department of Chemistry, University of Konstanz, Konstanz, Germany.
Verena Natalie
VN
Schreier
Department of Chemistry, University of Konstanz, Konstanz, Germany; MTA-ELTE Research Group of Peptide Chemistry, Budapest, Hungary.
Lilla
L
Pethő
MTA-ELTE Research Group of Peptide Chemistry, Budapest, Hungary.
Erika
E
Orbán
Proteomics Facility, University of Konstanz, Konstanz, Germany.
Andreas
A
Marquardt
Faculty of Chemistry, "Al. I. Cuza" University of Iasi, Iasi, Romania.
Brindusa Alina
BA
Petre
MTA-ELTE Research Group of Peptide Chemistry, Budapest, Hungary.
Gábor
G
Mező
Department of Chemistry, University of Konstanz, Konstanz, Germany; Zukunftskolleg, University of Konstanz, Konstanz, Germany.
Marilena
M
Manea
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003603:Cytotoxins / Q000494:pharmacology*; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D015180:Electrophoresis, Gel, Two-Dimensional; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D008099:Liver / Q000201:enzymology; D008247:Lysosomes / Q000201:enzymology; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats
D000970:Antineoplastic Agents; D003603:Cytotoxins; C000598596:GnRH-III, acetyllysyl(4)-(daunorubicin-aminooxyacetyl)lysyl(8)-; D009363:Neoplasm Proteins; D007987:Gonadotropin-Releasing Hormone; D003630:Daunorubicin