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Selective growth inhibition of human malignant melanoma cells by syringic acid-derived proteasome inhibitors
BACKGROUND: It has been shown that proteasome inhibition leads to growth arrest in the G1 phase of the cell cycle and/or induction of apoptosis. However, it was found that some of these inhibitors do not induce apoptosis in several human normal cell lines. This selective activity makes proteasome in...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765228/ https://www.ncbi.nlm.nih.gov/pubmed/23958424 http://dx.doi.org/10.1186/1475-2867-13-82 |
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author | Orabi, Khaled Y Abaza, Mohamed S El Sayed, Khalid A Elnagar, Ahmed Y Al-Attiyah, Rajaa Guleri, Radhika P |
author_facet | Orabi, Khaled Y Abaza, Mohamed S El Sayed, Khalid A Elnagar, Ahmed Y Al-Attiyah, Rajaa Guleri, Radhika P |
author_sort | Orabi, Khaled Y |
collection | PubMed |
description | BACKGROUND: It has been shown that proteasome inhibition leads to growth arrest in the G1 phase of the cell cycle and/or induction of apoptosis. However, it was found that some of these inhibitors do not induce apoptosis in several human normal cell lines. This selective activity makes proteasome inhibition a promising target for new generation of anticancer drugs. Clinical validation of the proteasome, as a therapeutic target in oncology, has been provided by the dipeptide boronic acid derivative; bortezomib. Bortezomib has proven to be effective as a single agent in multiple myeloma and some forms of non-Hodgkin’s lymphoma. Syringic acid (4-hydroxy-3,5-dimethoxybenzoic acid, 1), a known phenolic acid, was isolated from the methanol extract of Tamarix aucheriana and was shown to possess proteasome inhibitory activity. METHODS: Using Surflex-Dock program interfaced with SYBYL, the docking affinities of syringic acid and its proposed derivatives to 20S proteasome were studied. Several derivatives were virtually proposed, however, five derivatives: benzyl 4-hydroxy-3,5-dimethoxybenzoate (2), benzyl 4-(benzyloxy)-3,5-dimethoxybenzoate (3), 3'-methoxybenzyl 3,5-dimethoxy-4-(3'-methoxybenzyloxy)benzoate (4), 3'-methoxybenzyl 4-hydroxy-3,5-dimethoxybenzoate (5) and 3',5'-dimethoxybenzyl 4-hydroxy-3,5-dimethoxybenzoate (6), were selected based on high docking scores, synthesized, and tested for their anti-mitogenic activity against human colorectal, breast and malignant melanoma cells as well as normal human fibroblast cells. RESULTS: Derivatives 2, 5, and 6 showed selective dose-dependent anti-mitogenic effect against human malignant melanoma cell lines HTB66 and HTB68 with minimal cytotoxicity on colorectal and breast cancer cells as well as normal human fibroblast cells. Derivatives 2, 5 and 6 significantly (p ≤ 0.0001) inhibited the various proteasomal chymotrypsin, PGPH, and trypsin like activities. They growth arrested the growth of HTB66 cells at G1 and G2-phases. They also arrested the growth of HTB68 cells at S- and G2-phase, respectively. Moreover, derivatives 2, 5, and 6 markedly induced apoptosis (≥ 90%) in both HTB66 and HTB68. CONCLUSIONS: Computer-derived syringic acid derivatives possess selective anti-mitogenic activity on human malignant melanoma cells that may be attributed to perturbation of cell cycle, induction of apoptosis and inhibition of various 26S proteasomal activities. |
format | Online Article Text |
id | pubmed-3765228 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-37652282013-09-07 Selective growth inhibition of human malignant melanoma cells by syringic acid-derived proteasome inhibitors Orabi, Khaled Y Abaza, Mohamed S El Sayed, Khalid A Elnagar, Ahmed Y Al-Attiyah, Rajaa Guleri, Radhika P Cancer Cell Int Primary Research BACKGROUND: It has been shown that proteasome inhibition leads to growth arrest in the G1 phase of the cell cycle and/or induction of apoptosis. However, it was found that some of these inhibitors do not induce apoptosis in several human normal cell lines. This selective activity makes proteasome inhibition a promising target for new generation of anticancer drugs. Clinical validation of the proteasome, as a therapeutic target in oncology, has been provided by the dipeptide boronic acid derivative; bortezomib. Bortezomib has proven to be effective as a single agent in multiple myeloma and some forms of non-Hodgkin’s lymphoma. Syringic acid (4-hydroxy-3,5-dimethoxybenzoic acid, 1), a known phenolic acid, was isolated from the methanol extract of Tamarix aucheriana and was shown to possess proteasome inhibitory activity. METHODS: Using Surflex-Dock program interfaced with SYBYL, the docking affinities of syringic acid and its proposed derivatives to 20S proteasome were studied. Several derivatives were virtually proposed, however, five derivatives: benzyl 4-hydroxy-3,5-dimethoxybenzoate (2), benzyl 4-(benzyloxy)-3,5-dimethoxybenzoate (3), 3'-methoxybenzyl 3,5-dimethoxy-4-(3'-methoxybenzyloxy)benzoate (4), 3'-methoxybenzyl 4-hydroxy-3,5-dimethoxybenzoate (5) and 3',5'-dimethoxybenzyl 4-hydroxy-3,5-dimethoxybenzoate (6), were selected based on high docking scores, synthesized, and tested for their anti-mitogenic activity against human colorectal, breast and malignant melanoma cells as well as normal human fibroblast cells. RESULTS: Derivatives 2, 5, and 6 showed selective dose-dependent anti-mitogenic effect against human malignant melanoma cell lines HTB66 and HTB68 with minimal cytotoxicity on colorectal and breast cancer cells as well as normal human fibroblast cells. Derivatives 2, 5 and 6 significantly (p ≤ 0.0001) inhibited the various proteasomal chymotrypsin, PGPH, and trypsin like activities. They growth arrested the growth of HTB66 cells at G1 and G2-phases. They also arrested the growth of HTB68 cells at S- and G2-phase, respectively. Moreover, derivatives 2, 5, and 6 markedly induced apoptosis (≥ 90%) in both HTB66 and HTB68. CONCLUSIONS: Computer-derived syringic acid derivatives possess selective anti-mitogenic activity on human malignant melanoma cells that may be attributed to perturbation of cell cycle, induction of apoptosis and inhibition of various 26S proteasomal activities. BioMed Central 2013-08-19 /pmc/articles/PMC3765228/ /pubmed/23958424 http://dx.doi.org/10.1186/1475-2867-13-82 Text en Copyright © 2013 Orabi et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Primary Research Orabi, Khaled Y Abaza, Mohamed S El Sayed, Khalid A Elnagar, Ahmed Y Al-Attiyah, Rajaa Guleri, Radhika P Selective growth inhibition of human malignant melanoma cells by syringic acid-derived proteasome inhibitors |
title | Selective growth inhibition of human malignant melanoma cells by syringic acid-derived proteasome inhibitors |
title_full | Selective growth inhibition of human malignant melanoma cells by syringic acid-derived proteasome inhibitors |
title_fullStr | Selective growth inhibition of human malignant melanoma cells by syringic acid-derived proteasome inhibitors |
title_full_unstemmed | Selective growth inhibition of human malignant melanoma cells by syringic acid-derived proteasome inhibitors |
title_short | Selective growth inhibition of human malignant melanoma cells by syringic acid-derived proteasome inhibitors |
title_sort | selective growth inhibition of human malignant melanoma cells by syringic acid-derived proteasome inhibitors |
topic | Primary Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765228/ https://www.ncbi.nlm.nih.gov/pubmed/23958424 http://dx.doi.org/10.1186/1475-2867-13-82 |
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