Cargando…
Valproic Acid Downregulates the Expression of MGMT and Sensitizes Temozolomide-Resistant Glioma Cells
Temozolomide (TMZ) has become a key therapeutic agent in patients with malignant gliomas; however, its survival benefit remains unsatisfactory. Valproic acid (VPA) has emerged as an anticancer drug via inhibition of histone deacetylases (HDACs), but the therapeutic advantages of a combination with V...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi Publishing Corporation
2012
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3373250/ https://www.ncbi.nlm.nih.gov/pubmed/22701311 http://dx.doi.org/10.1155/2012/987495 |
_version_ | 1782235434391175168 |
---|---|
author | Ryu, Chung Heon Yoon, Wan Soo Park, Kwang Ywel Kim, Seong Muk Lim, Jung Yeon Woo, Ji Sun Jeong, Chang Hyun Hou, Yun Jeun, Sin-Soo |
author_facet | Ryu, Chung Heon Yoon, Wan Soo Park, Kwang Ywel Kim, Seong Muk Lim, Jung Yeon Woo, Ji Sun Jeong, Chang Hyun Hou, Yun Jeun, Sin-Soo |
author_sort | Ryu, Chung Heon |
collection | PubMed |
description | Temozolomide (TMZ) has become a key therapeutic agent in patients with malignant gliomas; however, its survival benefit remains unsatisfactory. Valproic acid (VPA) has emerged as an anticancer drug via inhibition of histone deacetylases (HDACs), but the therapeutic advantages of a combination with VPA and TMZ remain poorly understood. The main aim of the present study was to determine whether an antitumor effect could be potentiated by a combination of VPA and TMZ, especially in TMZ-resistant cell lines. A combination of VPA and TMZ had a significantly enhanced antitumor effect in TMZ-resistant malignant glioma cells (T98 and U138). This enhanced antitumor effect correlated with VPA-mediated reduced O6-methylguanine-DNA methyltransferase (MGMT) expression, which plays an important role in cellular resistance to alkylating agents. In vitro, the combination of these drugs enhanced the apoptotic and autophagic cell death, as well as suppressed the migratory activities in TMZ-resistant cell lines. Furthermore, in vivo efficacy experiment showed that treatment of combination of VPA and TMZ significantly inhibited tumor growth compared with the monotherapy groups of mice. These results suggest that the clinical efficacy of TMZ chemotherapy in TMZ-resistant malignant glioma may be improved by combination with VPA. |
format | Online Article Text |
id | pubmed-3373250 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Hindawi Publishing Corporation |
record_format | MEDLINE/PubMed |
spelling | pubmed-33732502012-06-14 Valproic Acid Downregulates the Expression of MGMT and Sensitizes Temozolomide-Resistant Glioma Cells Ryu, Chung Heon Yoon, Wan Soo Park, Kwang Ywel Kim, Seong Muk Lim, Jung Yeon Woo, Ji Sun Jeong, Chang Hyun Hou, Yun Jeun, Sin-Soo J Biomed Biotechnol Research Article Temozolomide (TMZ) has become a key therapeutic agent in patients with malignant gliomas; however, its survival benefit remains unsatisfactory. Valproic acid (VPA) has emerged as an anticancer drug via inhibition of histone deacetylases (HDACs), but the therapeutic advantages of a combination with VPA and TMZ remain poorly understood. The main aim of the present study was to determine whether an antitumor effect could be potentiated by a combination of VPA and TMZ, especially in TMZ-resistant cell lines. A combination of VPA and TMZ had a significantly enhanced antitumor effect in TMZ-resistant malignant glioma cells (T98 and U138). This enhanced antitumor effect correlated with VPA-mediated reduced O6-methylguanine-DNA methyltransferase (MGMT) expression, which plays an important role in cellular resistance to alkylating agents. In vitro, the combination of these drugs enhanced the apoptotic and autophagic cell death, as well as suppressed the migratory activities in TMZ-resistant cell lines. Furthermore, in vivo efficacy experiment showed that treatment of combination of VPA and TMZ significantly inhibited tumor growth compared with the monotherapy groups of mice. These results suggest that the clinical efficacy of TMZ chemotherapy in TMZ-resistant malignant glioma may be improved by combination with VPA. Hindawi Publishing Corporation 2012 2012-06-04 /pmc/articles/PMC3373250/ /pubmed/22701311 http://dx.doi.org/10.1155/2012/987495 Text en Copyright © 2012 Chung Heon Ryu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Ryu, Chung Heon Yoon, Wan Soo Park, Kwang Ywel Kim, Seong Muk Lim, Jung Yeon Woo, Ji Sun Jeong, Chang Hyun Hou, Yun Jeun, Sin-Soo Valproic Acid Downregulates the Expression of MGMT and Sensitizes Temozolomide-Resistant Glioma Cells |
title | Valproic Acid Downregulates the Expression of MGMT and Sensitizes Temozolomide-Resistant Glioma Cells |
title_full | Valproic Acid Downregulates the Expression of MGMT and Sensitizes Temozolomide-Resistant Glioma Cells |
title_fullStr | Valproic Acid Downregulates the Expression of MGMT and Sensitizes Temozolomide-Resistant Glioma Cells |
title_full_unstemmed | Valproic Acid Downregulates the Expression of MGMT and Sensitizes Temozolomide-Resistant Glioma Cells |
title_short | Valproic Acid Downregulates the Expression of MGMT and Sensitizes Temozolomide-Resistant Glioma Cells |
title_sort | valproic acid downregulates the expression of mgmt and sensitizes temozolomide-resistant glioma cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3373250/ https://www.ncbi.nlm.nih.gov/pubmed/22701311 http://dx.doi.org/10.1155/2012/987495 |
work_keys_str_mv | AT ryuchungheon valproicaciddownregulatestheexpressionofmgmtandsensitizestemozolomideresistantgliomacells AT yoonwansoo valproicaciddownregulatestheexpressionofmgmtandsensitizestemozolomideresistantgliomacells AT parkkwangywel valproicaciddownregulatestheexpressionofmgmtandsensitizestemozolomideresistantgliomacells AT kimseongmuk valproicaciddownregulatestheexpressionofmgmtandsensitizestemozolomideresistantgliomacells AT limjungyeon valproicaciddownregulatestheexpressionofmgmtandsensitizestemozolomideresistantgliomacells AT woojisun valproicaciddownregulatestheexpressionofmgmtandsensitizestemozolomideresistantgliomacells AT jeongchanghyun valproicaciddownregulatestheexpressionofmgmtandsensitizestemozolomideresistantgliomacells AT houyun valproicaciddownregulatestheexpressionofmgmtandsensitizestemozolomideresistantgliomacells AT jeunsinsoo valproicaciddownregulatestheexpressionofmgmtandsensitizestemozolomideresistantgliomacells |