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Thymoquinone induces apoptosis in temozolomide‐resistant glioblastoma cells via the p38 mitogen‐activated protein kinase signaling pathway

Temozolomide (TMZ) can cross the blood‐brain barrier (BBB) and deliver methyl groups to the purine (guanine) bases of DNA, leading to mispairing during DNA replication and subsequent cell death. However, increased expression of the repair enzyme methyl guanine methyltransferase (MGMT), which removes...

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Autores principales: Mai, Ai, Ye, Shu‐Wen, Tu, Jia‐Yu, Gao, Jun, Kang, Zhan‐Fang, Yao, Qian‐Ming, Ting, Wei‐Jen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10087852/
https://www.ncbi.nlm.nih.gov/pubmed/36176197
http://dx.doi.org/10.1002/tox.23664
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author Mai, Ai
Ye, Shu‐Wen
Tu, Jia‐Yu
Gao, Jun
Kang, Zhan‐Fang
Yao, Qian‐Ming
Ting, Wei‐Jen
author_facet Mai, Ai
Ye, Shu‐Wen
Tu, Jia‐Yu
Gao, Jun
Kang, Zhan‐Fang
Yao, Qian‐Ming
Ting, Wei‐Jen
author_sort Mai, Ai
collection PubMed
description Temozolomide (TMZ) can cross the blood‐brain barrier (BBB) and deliver methyl groups to the purine (guanine) bases of DNA, leading to mispairing during DNA replication and subsequent cell death. However, increased expression of the repair enzyme methyl guanine methyltransferase (MGMT), which removes methyl groups from purine bases, counteracts methylation by TMZ. We evaluated the anticancer potential of thymoquinone (TQ), a hydrophobic flavonoid that inhibits resistance and induces apoptosis in various cancer cells, both in vitro and in vivo. In vitro experiments showed that compared with the Hs683 and M059J cell lines, U251 cells were more sensitive to TMZ. Compared to U251 cells, U251R cells, a TMZ drug‐resistant strain established in this study, are characterized by increased expression of phosphorylated extracellular signal‐regulated kinase (p‐ERK) and MGMT. TQ treatments induced apoptosis in all cell lines. The p38 mitogen‐activated protein kinase signal pathway was mainly activated in U251 and U251R cells; however, p‐ERK and MGMT upregulation could not suppress TQ effects. Furthermore, si‐p38 pretreatment of U251R cells in TQ treatments inhibited cell apoptosis. We speculate that TQ contributed to the phosphorylation and activation of p38, but not of ERK‐induced apoptosis (irrespective of TMZ resistance). In vivo, U251R‐derived tumors subcutaneously inoculated in nude mice exhibited significant tumor volume reduction after TQ or TQ + TMZ cotreatments. High‐performance liquid chromatography assay confirmed the presence of TQ in murine brain tissues. Our findings demonstrate that TQ can effectively cross the BBB and function alone or in combination with TMZ to treat glioblastoma.
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spelling pubmed-100878522023-04-12 Thymoquinone induces apoptosis in temozolomide‐resistant glioblastoma cells via the p38 mitogen‐activated protein kinase signaling pathway Mai, Ai Ye, Shu‐Wen Tu, Jia‐Yu Gao, Jun Kang, Zhan‐Fang Yao, Qian‐Ming Ting, Wei‐Jen Environ Toxicol Research Articles Temozolomide (TMZ) can cross the blood‐brain barrier (BBB) and deliver methyl groups to the purine (guanine) bases of DNA, leading to mispairing during DNA replication and subsequent cell death. However, increased expression of the repair enzyme methyl guanine methyltransferase (MGMT), which removes methyl groups from purine bases, counteracts methylation by TMZ. We evaluated the anticancer potential of thymoquinone (TQ), a hydrophobic flavonoid that inhibits resistance and induces apoptosis in various cancer cells, both in vitro and in vivo. In vitro experiments showed that compared with the Hs683 and M059J cell lines, U251 cells were more sensitive to TMZ. Compared to U251 cells, U251R cells, a TMZ drug‐resistant strain established in this study, are characterized by increased expression of phosphorylated extracellular signal‐regulated kinase (p‐ERK) and MGMT. TQ treatments induced apoptosis in all cell lines. The p38 mitogen‐activated protein kinase signal pathway was mainly activated in U251 and U251R cells; however, p‐ERK and MGMT upregulation could not suppress TQ effects. Furthermore, si‐p38 pretreatment of U251R cells in TQ treatments inhibited cell apoptosis. We speculate that TQ contributed to the phosphorylation and activation of p38, but not of ERK‐induced apoptosis (irrespective of TMZ resistance). In vivo, U251R‐derived tumors subcutaneously inoculated in nude mice exhibited significant tumor volume reduction after TQ or TQ + TMZ cotreatments. High‐performance liquid chromatography assay confirmed the presence of TQ in murine brain tissues. Our findings demonstrate that TQ can effectively cross the BBB and function alone or in combination with TMZ to treat glioblastoma. John Wiley & Sons, Inc. 2022-09-29 2023-01 /pmc/articles/PMC10087852/ /pubmed/36176197 http://dx.doi.org/10.1002/tox.23664 Text en © 2022 The Authors. Environmental Toxicology published by Wiley Periodicals LLC. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Mai, Ai
Ye, Shu‐Wen
Tu, Jia‐Yu
Gao, Jun
Kang, Zhan‐Fang
Yao, Qian‐Ming
Ting, Wei‐Jen
Thymoquinone induces apoptosis in temozolomide‐resistant glioblastoma cells via the p38 mitogen‐activated protein kinase signaling pathway
title Thymoquinone induces apoptosis in temozolomide‐resistant glioblastoma cells via the p38 mitogen‐activated protein kinase signaling pathway
title_full Thymoquinone induces apoptosis in temozolomide‐resistant glioblastoma cells via the p38 mitogen‐activated protein kinase signaling pathway
title_fullStr Thymoquinone induces apoptosis in temozolomide‐resistant glioblastoma cells via the p38 mitogen‐activated protein kinase signaling pathway
title_full_unstemmed Thymoquinone induces apoptosis in temozolomide‐resistant glioblastoma cells via the p38 mitogen‐activated protein kinase signaling pathway
title_short Thymoquinone induces apoptosis in temozolomide‐resistant glioblastoma cells via the p38 mitogen‐activated protein kinase signaling pathway
title_sort thymoquinone induces apoptosis in temozolomide‐resistant glioblastoma cells via the p38 mitogen‐activated protein kinase signaling pathway
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10087852/
https://www.ncbi.nlm.nih.gov/pubmed/36176197
http://dx.doi.org/10.1002/tox.23664
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