A Novel Hydroxamic Acid-Based Curcumin Derivative as Potent Histone Deacetylase Inhibitor for the Treatment of Glioblastoma

Glioblastoma (GBM) is one of the most common primary and deadliest malignant brain tumor with chemoresistance and poor prognosis. There is a lack of effective chemotherapeutic drug for the treatment of GBM. In this work, we reported the preparation of a histone deacetylase (HDAC) inhibitor, DMC-HA,...

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Autores principales:	Hao Wang, Lei Shi, Zhimin Wang
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	derivative glioblastoma histone deacetylase inhibitor curcumin hydroxamic acid Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/2a623b45d799404f8abce9b4458c3db7
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spelling	oai:doaj.org-article:2a623b45d799404f8abce9b4458c3db72021-11-05T09:36:12ZA Novel Hydroxamic Acid-Based Curcumin Derivative as Potent Histone Deacetylase Inhibitor for the Treatment of Glioblastoma2234-943X10.3389/fonc.2021.756817https://doaj.org/article/2a623b45d799404f8abce9b4458c3db72021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.756817/fullhttps://doaj.org/toc/2234-943XGlioblastoma (GBM) is one of the most common primary and deadliest malignant brain tumor with chemoresistance and poor prognosis. There is a lack of effective chemotherapeutic drug for the treatment of GBM. In this work, we reported the preparation of a histone deacetylase (HDAC) inhibitor, DMC-HA, from the structural modification of natural product curcumin. DMC-HAs were tested in an HDAC inhibition assay and an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for cytotoxicity. It showed potent inhibition of HDAC1–2 and HDAC6 with IC50 values in the submicromolar concentration range. DMC-HA significantly inhibited the proliferation of human glioblastoma U87 cells and mediated apoptosis of U87 cells in a dose- and time-dependent manner. In addition, DMC-HA elevated the acetylation level of histone H3 in U87 cells. Pharmacokinetic studies showed that DMC-HA possessed acceptable pharmacokinetic profiles, accompanied with certain brain permeability. Lastly, we showed that DMC-HA suppressed the growth of tumor in U87 tumor xenograft model in vivo with no obvious toxicity. These results demonstrate that DMC-HA has the potential to be developed as a chemotherapeutic drug for GBM patients.Hao WangLei ShiZhimin WangFrontiers Media S.A.articlederivativeglioblastomahistone deacetylase inhibitorcurcuminhydroxamic acidNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	derivative glioblastoma histone deacetylase inhibitor curcumin hydroxamic acid Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	derivative glioblastoma histone deacetylase inhibitor curcumin hydroxamic acid Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Hao Wang Lei Shi Zhimin Wang A Novel Hydroxamic Acid-Based Curcumin Derivative as Potent Histone Deacetylase Inhibitor for the Treatment of Glioblastoma
description	Glioblastoma (GBM) is one of the most common primary and deadliest malignant brain tumor with chemoresistance and poor prognosis. There is a lack of effective chemotherapeutic drug for the treatment of GBM. In this work, we reported the preparation of a histone deacetylase (HDAC) inhibitor, DMC-HA, from the structural modification of natural product curcumin. DMC-HAs were tested in an HDAC inhibition assay and an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for cytotoxicity. It showed potent inhibition of HDAC1–2 and HDAC6 with IC50 values in the submicromolar concentration range. DMC-HA significantly inhibited the proliferation of human glioblastoma U87 cells and mediated apoptosis of U87 cells in a dose- and time-dependent manner. In addition, DMC-HA elevated the acetylation level of histone H3 in U87 cells. Pharmacokinetic studies showed that DMC-HA possessed acceptable pharmacokinetic profiles, accompanied with certain brain permeability. Lastly, we showed that DMC-HA suppressed the growth of tumor in U87 tumor xenograft model in vivo with no obvious toxicity. These results demonstrate that DMC-HA has the potential to be developed as a chemotherapeutic drug for GBM patients.
format	article
author	Hao Wang Lei Shi Zhimin Wang
author_facet	Hao Wang Lei Shi Zhimin Wang
author_sort	Hao Wang
title	A Novel Hydroxamic Acid-Based Curcumin Derivative as Potent Histone Deacetylase Inhibitor for the Treatment of Glioblastoma
title_short	A Novel Hydroxamic Acid-Based Curcumin Derivative as Potent Histone Deacetylase Inhibitor for the Treatment of Glioblastoma
title_full	A Novel Hydroxamic Acid-Based Curcumin Derivative as Potent Histone Deacetylase Inhibitor for the Treatment of Glioblastoma
title_fullStr	A Novel Hydroxamic Acid-Based Curcumin Derivative as Potent Histone Deacetylase Inhibitor for the Treatment of Glioblastoma
title_full_unstemmed	A Novel Hydroxamic Acid-Based Curcumin Derivative as Potent Histone Deacetylase Inhibitor for the Treatment of Glioblastoma
title_sort	novel hydroxamic acid-based curcumin derivative as potent histone deacetylase inhibitor for the treatment of glioblastoma
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/2a623b45d799404f8abce9b4458c3db7
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A Novel Hydroxamic Acid-Based Curcumin Derivative as Potent Histone Deacetylase Inhibitor for the Treatment of Glioblastoma

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