A new daunomycin–peptide conjugate : synthesis, characterization and the effect on the protein expression profile of HL-60 cells in vitro

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2011
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Orbán, Erika
Bánóczi, Zoltán
Csı́k, Gabriella
Fellinger, Erzsébet
Bősze, Szilvia
Hudecz, Ferenc
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Bioconjugate Chemistry. 2011, 22(10), pp. 2154-2165. ISSN 1043-1802. eISSN 1520-4812. Available under: doi: 10.1021/bc2004236
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Daunomycin (Dau) is a DNA-binding antineoplastic agent in the treatment of various types of cancer, such as osteosarcomas and acute myeloid leukemia. One approach to improve its selectivity and to decrease the side effects is the conjugation of Dau with oligopeptide carriers, which might alter the drug uptake and intracellular fate. Here, we report on the synthesis, characterization, and in vitro biological properties of a novel conjugate in which Dau is attached, via an oxime bond, to one of the cancer specific small peptides (LTVSPWY) selected from a random phage peptide library. The in vitro cytostatic effect and cellular uptake of Dau═Aoa-LTVSPWY-NH2 conjugate were studied on various human cancer cell lines expressing different levels of ErbB2 receptor which could be targeted by the peptide. We found that the new daunomycin–peptide conjugate is highly cytostatic and could be taken up efficiently by the human cancer cells studied. However, the conjugate was less effective than the free drug itself. RP-HPLC data indicate that the conjugate is stable at least for 24 h in the pH 2.5–7.0 range of buffers, as well as in cell culture medium. The conjugate in the presence of rat liver lysosomal homogenate, as indicated by LC-MS analysis, could be degraded. The smallest, Dau-containing metabolite (Dau═Aoa-Leu-OH) identified and prepared expresses DNA-binding ability. In order to get insight on the potential mechanism of action, we compared the protein expression profile of HL-60 human leukemia cells after treatment with the free and peptide conjugated daunomycin. Proteomic analysis suggests that the expression of several proteins has been altered. This includes three proteins, whose expression was lower (tubulin β chain) or markedly higher (proliferating cell nuclear antigen and protein kinase C inhibitor protein 1) after administration of cells with Dau-conjugate vs free drug.

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ISO 690ORBÁN, Erika, Marilena MANEA, Andreas MARQUARDT, Zoltán BÁNÓCZI, Gabriella CSÍK, Erzsébet FELLINGER, Szilvia BŐSZE, Ferenc HUDECZ, 2011. A new daunomycin–peptide conjugate : synthesis, characterization and the effect on the protein expression profile of HL-60 cells in vitro. In: Bioconjugate Chemistry. 2011, 22(10), pp. 2154-2165. ISSN 1043-1802. eISSN 1520-4812. Available under: doi: 10.1021/bc2004236
BibTex
@article{Orban2011-10-19dauno-17240,
  year={2011},
  doi={10.1021/bc2004236},
  title={A new daunomycin–peptide conjugate : synthesis, characterization and the effect on the protein expression profile of HL-60 cells in vitro},
  number={10},
  volume={22},
  issn={1043-1802},
  journal={Bioconjugate Chemistry},
  pages={2154--2165},
  author={Orbán, Erika and Manea, Marilena and Marquardt, Andreas and Bánóczi, Zoltán and Csı́k, Gabriella and Fellinger, Erzsébet and Bősze, Szilvia and Hudecz, Ferenc}
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