title: Hypoxia-activated cytotoxicity of benznidazole against clonogenic tumor cells.
abstract: Solid tumors contain numerous regions with insufficient oxygen concentrations, a condition termed hypoxia. Tumor hypoxia is significantly associated with metastasis, refractory to conventional cancer therapies, and poor patient survival. Therefore, eradication of hypoxic tumor cells will likely have significant impact on the overall progression-free patient survival. This article reports a new discovery that Benznidazole, a bioreductive drug currently used to treat Chagas disease caused by the parasitic protozoan Trypanosoma cruzi, is activated by hypoxia and can kill clonogenic tumor cells especially those under severe hypoxic conditions (≤0.1 % O2). This type of hypoxia selectivity is important in that severely hypoxic tumor microenvironment is where tumor cells exhibit the strongest resistance to therapy. Mechanistically, activation of Benznidazole coincides with the stabilization of the Hypoxia-Inducible Factor 1α (HIF-1α), suggesting that Benznidazole is activated after tumor cells have entered into a fully hypoxic state. Under such hypoxic conditions, Benznidazole induces the formation of 53BP1 foci, a hallmark of DNA double-stranded breaks that can cause clonogenic inhibition or cell death. These results demonstrate that Benznidazole is a hypoxia-activated cytotoxin with the potential to specifically eliminate hypoxic tumor cells.
authors: a Department of Therapeutic Radiology , Yale School of Medicine , New Haven , CT , USA.
authors: Quhuan
authors: Q
authors: Li
authors: a Department of Therapeutic Radiology , Yale School of Medicine , New Haven , CT , USA.
authors: Qun
authors: Q
authors: Lin
authors: a Department of Therapeutic Radiology , Yale School of Medicine , New Haven , CT , USA.
authors: Zhong
authors: Z
authors: Yun
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D045325:HCT116 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D009593:Nitroimidazoles / Q000494:pharmacology*; D059016:Tumor Microenvironment / Q000502:physiology*; D014410:Tumor Stem Cell Assay
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009593:Nitroimidazoles; C009999:benzonidazole
keywords: 53BP1; Benznidazole; DNA damage; PARP cleavage; clonogenic growth; hypoxia; nuclear foci