Abstract
The paper presents a detailed study of the biological effects of two amino acid hydroxyurea derivatives that showed selective antiproliferative effects in vitro on the growth of human tumor cell line SW620. Tested compounds induced cell cycle perturbations and apoptosis. Proteins were identified by proteomics analyses using two-dimensional gel electrophoresis coupled to mass spectrometry, which provided a complete insight into the most probable mechanism of action on the protein level. Molecular targets for tested compounds were analyzed by cheminformatics tools. Zinc-dependent histone deacetylases were identified as potential targets responsible for the observed antiproliferative effect.
Highlights
Colorectal cancer (CRC) is among the three most common malignancies worldwide, including breast and lung cancers
We have previously shown that BOU and MHCU exerted the strongest antiproliferative effect upon a panel of tested cell lines, including the metastatic colon cancer cell line SW620 [6,7]
Tested compounds are both amino acid derivatives of HU, with the same amide moiety and a different amino acid part: BOU is a D-phenylglycine and MHCU is a L-phenylalanine derivative. They differ in the HU section: MHCU has a free hydroxy group, while the hydroxy group in BOU is protected by the benzyl residue
Summary
Colorectal cancer (CRC) is among the three most common malignancies worldwide, including breast and lung cancers. Current drugs do not target this particular subset of cells and novel therapeutic approaches, including novel drug entities, are interesting for advancements in CRC treatment. Hydroxyurea (HU) is a common antimetabolic cytostatic compound used to treat some types of cancer (Figure 1A) and a number of its derivatives exerting stronger antitumor potency and lower general cytotoxicity have been synthesized [5]. Perkovic et al [6] synthesized a series of novel L- and D-amino acid amide HU derivatives and evaluated their antiviral and cytostatic activity against malignant tumor cell lines, including leukemia and normal human fibroblasts [6]. The selected compounds, N'-benzyloxycarbamoyl-D-phenylglycine benzhydrylamide (BOU) and N'-methylN'-hydroxycarbamoyl-L-phenylalanine benzhydrylamide (MHCU), shown, acted selectively on the colon tumor cell line SW620 in comparison with other tested tumor cell lines and normal human fibroblasts The selected compounds, N'-benzyloxycarbamoyl-D-phenylglycine benzhydrylamide (BOU) and N'-methylN'-hydroxycarbamoyl-L-phenylalanine benzhydrylamide (MHCU), shown in Figure 1A, acted selectively on the colon tumor cell line SW620 in comparison with other tested tumor cell lines and normal human fibroblasts
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