Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 20, Issue 18, Pages -Publisher
MDPI
DOI: 10.3390/ijms20184421
Keywords
gonadotropin-releasing hormone; butyrate; conjugation; drug-targeting conjugates; impedimetry; daunorubicin; apoptosis; TP53; TNF; FASL
Funding
- National Research, Development and Innovation Office [NKFIH K119552, NVKP_16-1-2016-0036]
- Development and Innovation Office [NVKP_16-1-2016-0036]
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The wide range of cellular target reactions (e.g., antitumor) of gonadotropin-releasing hormone (GnRH) variants provides the possibility to develop multifunctional GnRH conjugates. The aim of our work was to compare the cytotoxic/apoptotic activity of different GnRH-based, daunorubicin (Dau)-linked conjugates with or without butyrated Lys in position 4 ((4)Lys(Bu)) at a molecular level in a human colorectal carcinoma cell line. Cell viability was measured by impedimetry, cellular uptake and apoptosis were studied by flow cytometry, and the expression of apoptosis-related genes was analyzed by qRT-PCR. The modification with (4)Lys(Bu) resulted in an increased cytotoxic and apoptotic effects and cellular uptake of the GnRH-I and GnRH-III conjugates. Depending on the GnRH isoform and the presence of (4)Lys(Bu), the conjugates could regulate the expression of several apoptosis-related genes, especially tumor necrosis factor (TNF), tumor protein p53 (TP53) and the members of growth-factor signaling. The stronger cytotoxicity of GnRH-I and GnRH-III conjugates containing (4)Lys(Bu) was associated with a stronger inhibitory effect on the expression of growth-factor signaling elements in comparison with their (4)Ser counterparts, in which the upregulation of TP53 and caspases (e.g., CASP9) seemed to play a more important role. We were able to provide further evidence that targeting the GnRH receptor could serve as a successful therapeutic approach in colon cancer, and GnRH-III-[(4)Lys(Bu),(8)Lys(Dau=Aoa)] proved to be the best candidate for this purpose.
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