Abstract
In spite of the tremendous efforts dedicated to developing hypoxia-activated prodrugs, no agents yet have been approved for clinical therapy. In the present study, the hypoxic selective anti-cancer activity as well as the cellular target of a novel tirapazamine (TPZ) analogue, 7-methyl-3-(3-chlorophenyl)-quinoxaline-2-carbonitrile 1,4-dioxide (Q6) were investigated. Q6 implemented anti-cancer effects via poisoning topoisomerase II (topo II) under hypoxia. Modified trapped in agarose DNA immunostaining (TARDIS) assay showed more topo II–DNA cleavage complexes trapped by Q6 than TPZ at even lower concentration. In addition, by introducing ataxia-telangiectasia-mutated (ATM) kinase inhibitors caffeine and KU-60019, we displayed that Q6-triggered apoptosis was attributed, at least partially, to DNA double-strand breaks generated by the topo II-targeting effect. Collectively, Q6 stood out for its better hypoxia-selectivity and topo II-poisoning than the parental compound TPZ. All these data shed light on the research of Q6 as a promising hypoxia-activated prodrug candidate for human hepatocellular carcinoma therapy.
Highlights
A hallmark of solid tumor is hypoxia, which partially attributes to the outgrowth of cancer cells
It was evaluated in human hepatocellular carcinoma, with IC50 of 2.23 μM for Bel-7402 in hypoxia, 14.7 μM in normoxia, and with IC50 of 1.76 μM for HepG2 in hypoxia, 13.1 μM in normoxia
The exposure to Q6 (1 μM, 72 h) caused much more dead cell poplulation on hypoxia-cultured HCC cell lines HepG2 (47%), Bel-7402(43%) and SMMC-7721 (69%), than that of normoxic HepG2 (7%), Bel-7402(8%) and SMMC-7721 (7%). Those hypoxic HCC cells treated with Q6 exhibit a shrunken and round morphology as compared with those of control groups (0 μM) (Fig 1B). These results suggest that Q6 might be a promising drug candidate for further development as a hypoxic selective anti-tumor agent to treat hepatocellular carcinoma
Summary
A hallmark of solid tumor is hypoxia, which partially attributes to the outgrowth of cancer cells. Mounting evidences indicate that hypoxia confers highly resistance to conventional chemotherapy and radiation therapy. Hypoxia is thought to promote invasiveness and metastasis, usually correlated with poor patient prognosis. As a physiological feature of solid tumor, hypoxia has shed light on targeting therapy, namely, developing hypoxia-activated prodrugs (HAPs). HAPs predominantly share a common mechanism that can be reduced to covalent modifiers of DNA in hypoxic cells [1], exhibiting toxic side effects to hypoxic cells and reduced side effects to normoxic cells.
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