Development and biological evaluation of AzoBGNU: A novel hypoxia-activated DNA crosslinking prodrug with AGT-inhibitory activity

Chloroethylnitrosoureas (CENUs) are an important family of chemotherapies in clinical treatment of cancers, which exert antitumor activity by inducing the formation of DNA interstrand crosslinks (dG-dC ICLs). However, the drug resistance mediated by O6-alkylguanine-DNA alkyltransferase (AGT) and abs...

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Autores principales:	Qi Liu, Xiaoli Wang, Jun Li, Jiaojiao Wang, Guohui Sun, Na Zhang, Ting Ren, Lijiao Zhao, Rugang Zhong
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	chloroethylnitrosoureas tumor targeting hypoxia-activated prodrug DNA interstrand crosslinks drug resistance O6-alkylguanine DNA alkyltransferase Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/6f5f40a33b0a4ab188c31bc1717591da
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spelling	oai:doaj.org-article:6f5f40a33b0a4ab188c31bc1717591da2021-11-14T04:29:59ZDevelopment and biological evaluation of AzoBGNU: A novel hypoxia-activated DNA crosslinking prodrug with AGT-inhibitory activity0753-332210.1016/j.biopha.2021.112338https://doaj.org/article/6f5f40a33b0a4ab188c31bc1717591da2021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0753332221011227https://doaj.org/toc/0753-3322Chloroethylnitrosoureas (CENUs) are an important family of chemotherapies in clinical treatment of cancers, which exert antitumor activity by inducing the formation of DNA interstrand crosslinks (dG-dC ICLs). However, the drug resistance mediated by O6-alkylguanine-DNA alkyltransferase (AGT) and absence of tumor-targeting ability largely decrease the antitumor efficacy of CENUs. In this study, we synthesized an azobenzene-based hypoxia-activated combi-nitrosourea prodrug, AzoBGNU, and evaluated its hypoxic selectivity and antitumor activity. The prodrug was composed of a CENU pharmacophore and an O6-benzylguanine (O6-BG) analog moiety masked by a N,N-dimethyl-4-(phenyldiazenyl)aniline segment as a hypoxia-activated trigger, which was designed to be selectively reduced via azo bond break in hypoxic tumor microenvironment, accompanied with releasing of an O6-BG analog to inhibit AGT and a chloroethylating agent to induce dG-dC ICLs. AzoBGNU exhibited significantly increased cytotoxicity and apoptosis-inducing ability toward DU145 cells under hypoxia compared with normoxia, indicating the hypoxia-responsiveness as expected. Predominant higher cytotoxicity was observed in the cells treated by AzoBGNU than those by traditional CENU chemotherapy ACNU and its combination with O6-BG. The levels of dG-dC ICLs in DU145 cells induced by AzoBGNU was remarkably enhanced under hypoxia, which was approximately 6-fold higher than those in the AzoBGNU-treated groups under normoxia and those in the ACNU-treated groups. The results demonstrated that azobenzene-based combi-nitrosourea prodrug possessed desirable tumor-hypoxia targeting ability and eliminated chemoresistance compared with the conventional CENUs.Qi LiuXiaoli WangJun LiJiaojiao WangGuohui SunNa ZhangTing RenLijiao ZhaoRugang ZhongElsevierarticlechloroethylnitrosoureastumor targetinghypoxia-activated prodrugDNA interstrand crosslinksdrug resistanceO6-alkylguanine DNA alkyltransferaseTherapeutics. PharmacologyRM1-950ENBiomedicine & Pharmacotherapy, Vol 144, Iss , Pp 112338- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	chloroethylnitrosoureas tumor targeting hypoxia-activated prodrug DNA interstrand crosslinks drug resistance O6-alkylguanine DNA alkyltransferase Therapeutics. Pharmacology RM1-950
spellingShingle	chloroethylnitrosoureas tumor targeting hypoxia-activated prodrug DNA interstrand crosslinks drug resistance O6-alkylguanine DNA alkyltransferase Therapeutics. Pharmacology RM1-950 Qi Liu Xiaoli Wang Jun Li Jiaojiao Wang Guohui Sun Na Zhang Ting Ren Lijiao Zhao Rugang Zhong Development and biological evaluation of AzoBGNU: A novel hypoxia-activated DNA crosslinking prodrug with AGT-inhibitory activity
description	Chloroethylnitrosoureas (CENUs) are an important family of chemotherapies in clinical treatment of cancers, which exert antitumor activity by inducing the formation of DNA interstrand crosslinks (dG-dC ICLs). However, the drug resistance mediated by O6-alkylguanine-DNA alkyltransferase (AGT) and absence of tumor-targeting ability largely decrease the antitumor efficacy of CENUs. In this study, we synthesized an azobenzene-based hypoxia-activated combi-nitrosourea prodrug, AzoBGNU, and evaluated its hypoxic selectivity and antitumor activity. The prodrug was composed of a CENU pharmacophore and an O6-benzylguanine (O6-BG) analog moiety masked by a N,N-dimethyl-4-(phenyldiazenyl)aniline segment as a hypoxia-activated trigger, which was designed to be selectively reduced via azo bond break in hypoxic tumor microenvironment, accompanied with releasing of an O6-BG analog to inhibit AGT and a chloroethylating agent to induce dG-dC ICLs. AzoBGNU exhibited significantly increased cytotoxicity and apoptosis-inducing ability toward DU145 cells under hypoxia compared with normoxia, indicating the hypoxia-responsiveness as expected. Predominant higher cytotoxicity was observed in the cells treated by AzoBGNU than those by traditional CENU chemotherapy ACNU and its combination with O6-BG. The levels of dG-dC ICLs in DU145 cells induced by AzoBGNU was remarkably enhanced under hypoxia, which was approximately 6-fold higher than those in the AzoBGNU-treated groups under normoxia and those in the ACNU-treated groups. The results demonstrated that azobenzene-based combi-nitrosourea prodrug possessed desirable tumor-hypoxia targeting ability and eliminated chemoresistance compared with the conventional CENUs.
format	article
author	Qi Liu Xiaoli Wang Jun Li Jiaojiao Wang Guohui Sun Na Zhang Ting Ren Lijiao Zhao Rugang Zhong
author_facet	Qi Liu Xiaoli Wang Jun Li Jiaojiao Wang Guohui Sun Na Zhang Ting Ren Lijiao Zhao Rugang Zhong
author_sort	Qi Liu
title	Development and biological evaluation of AzoBGNU: A novel hypoxia-activated DNA crosslinking prodrug with AGT-inhibitory activity
title_short	Development and biological evaluation of AzoBGNU: A novel hypoxia-activated DNA crosslinking prodrug with AGT-inhibitory activity
title_full	Development and biological evaluation of AzoBGNU: A novel hypoxia-activated DNA crosslinking prodrug with AGT-inhibitory activity
title_fullStr	Development and biological evaluation of AzoBGNU: A novel hypoxia-activated DNA crosslinking prodrug with AGT-inhibitory activity
title_full_unstemmed	Development and biological evaluation of AzoBGNU: A novel hypoxia-activated DNA crosslinking prodrug with AGT-inhibitory activity
title_sort	development and biological evaluation of azobgnu: a novel hypoxia-activated dna crosslinking prodrug with agt-inhibitory activity
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/6f5f40a33b0a4ab188c31bc1717591da
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Development and biological evaluation of AzoBGNU: A novel hypoxia-activated DNA crosslinking prodrug with AGT-inhibitory activity

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