Development and biological evaluation of AzoBGNU: A novel hypoxia-activated DNA crosslinking prodrug with AGT-inhibitory activity - 13/11/21
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Abstract |
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.
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Highlights |
• | AzoBGNU is a tumor hypoxia targeting combi-nitrosourea prodrug containing a azobenzene moiety as a hypoxia trigger. |
• | The prodrug selectively inhibits AGT activity in hypoxic tumor microenvironment and leads to high cytotoxicity. |
• | The azo bond break of the azobenzene group triggers the hypoxia-response of AzoBGNU. |
• | AzoBGNU induces higher cytotoxicity, apoptosis and DNA crosslinking levels under hypoxia than normoxia. |
• | AzoBGNU shows hypoxia selectivity and improved anticancer efficacy than classical CENUs. |
Keywords : chloroethylnitrosoureas, tumor targeting, hypoxia-activated prodrug, DNA interstrand crosslinks, drug resistance, O6-alkylguanine DNA alkyltransferase
Plan
Vol 144
Article 112338- décembre 2021 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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