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Chemosensitization of Prostate Carcinoma Cells with a Receptor-directed Smac Conjugate

[ Vol. 12 , Issue. 5 ]

Author(s):

Alexander Sturzu, Sumbla Sheikh, Hartmut Echner, Martin Deeg, Thomas Nägele, Christopher Weidenmaier, Christian Schwentner, Marius Horger, Ulrike Ernemann and Stefan Heckl   Pages 412 - 418 ( 7 )

Abstract:


Background: Second mitochondrial activator of caspase (Smac) is a short mitochondrial peptide. When released from the mitochondria into the cytoplasm, it binds to inhibitor of apoptotic proteins (IAPs) within the cytoplasm and prevents them from inhibiting apoptosis.

Objective: Delivery of external synthetic Smac peptide into the cytoplasm of malignant cells could greatly improve the efficiency of apoptosis-inducing chemotherapeutic agents.

Method: In our study different conjugates based on the seven N-terminal amino acids AVPIAQK of Smac (SmacN7) were produced to obtain a cytoplasm-directed Smac variant. SmacN7 and a point mutant (AVPKAQK) were coupled either to rhodamine alone or to both rhodamine and undecylic aldehyde, which is an antagonist of the Lily-of-the-valley fragrance receptor. The fifth conjugate consisted of rhodamine coupled only to undecylic aldehyde, without SmacN7. The uptake of these five conjugates into three different human cell lines was characterized and quantified by confocal laser scanning microscopy and flow cytometry. A caspase apoptosis assay was performed for cells incubated with the five different conjugates after induction of apoptosis.

Results: The coupling of undecylic aldehyde to SmacN7 increased the cellular uptake of the correct and mutant conjugates.

Conclusion: Caspase 3/7 apoptosis tests after induction of apoptosis with staurosporine or UV irradiation showed that the coupling of SmacN7 with undecylic aldehyde resulted in a greatly increased adjuvant pro-apoptotic effect compared to the separate components and a mutant SmacN7 peptide sequence in the LNCaP prostate carcinoma cells compared to the benign prostate hyperplasia (BPH) cells and the human embryonal kidney (HEK) cells.

Keywords:

Prostate carcinoma, apoptosis, Smac conjugates, undecylic aldehyde, human odorant receptor.

Affiliation:

Department of Neuroradiology University of Tübingen Hoppe-Seyler-Str.3 72076 Tübingen, Germany



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