Abstract
The study presented here is a follow up of the authors’ interest in the approach to selective and cytotoxic bioreductive anticancer prodrugs. The current work is devoted to explore both the biological activity of some previously obtained compounds and the search for an explanation of their target(s) in hypoxic pathways. In this work the biological activity of some benzimidazole-4,7-diones was evaluated. These compounds were examined as potential bioreductive agents specific for the hypoxic environment found in tumor cells. The main aim was concerned with establishing their cytotoxic properties by using proliferation, apoptosis and DNA destruction tests on selected tumor cells. Their cytotoxic effects on two tumor cell lines (human lung adenocarcinoma A549 cells line and human malignant melanoma WM115) was compared by means of a WST-1 test. Next, the mode of cytotoxicity behind the selected tumor cells’ death was determined by the caspase 3/7 test. The last point referred to the DNA destruction of A549 and WM115 cells and the in situ DNA Assay Kit test was applied. The cytotoxic tests confirmed their activity against the tumor cells and target hypoxia (compounds 2b, 2a, 2d). The screening test of the caspase-dependent apoptosis proved that the exposure of the tested tumor cells in hypoxia to these benzimidazole-4,7-diones promoted the apoptotic cell death. Additionally, the DNA damage test established that benzimidazole-4,7-diones can be potential hypoxia-selective agents for tumor cells, especially compound 2b. All results classify the tested benzimidazole-4,7-diones as promising, lead molecules and provide a rationale for further molecular studies to explain their usefulness as potential inhibitors of the hypoxia-inducible factor 1 (HIF1).
Highlights
A new approach in the anticancer therapy concerns the use of bioreductive agents as prodrugs specific for tumor cells with very low oxygen concentration
We worked out conditions for obtaining benzimidazole-4,7-dione derivatives 1a–d and N-oxide benzimidazole-4,7-dione derivatives 2a–d as we described earlier [20]
The human lung adenocarcinoma A549 line and human malignant melanoma WM115 line were used for investigating in vitro the anticancer activity of the synthesized benzimidazole-4,7-dione derivatives 1, 2
Summary
A new approach in the anticancer therapy concerns the use of bioreductive agents as prodrugs specific for tumor cells with very low oxygen concentration. The potential for using quinones as bioreductive prodrugs emerged with the discovery that the anticancer antibiotic mitomycin C causes DNA-crosslinking which is activated by reducing its indoloquinone moiety [2] As activation of this drug is inhibited by an oxidizing environment, it was thought that mitomycin C would have selective toxicity for hypoxic solid tumours, and potently suppress their growth [4]. Derivatives which contain the benzimidazole ring act as human DNA topoisomerase I [12,13,14] inhibitors and are expected to possess anticancer properties [15] and affinity which is selective for cells under hypoxic conditions [12] In this context, benzimidazole-4,7-diones derivatives play an important role as quinones are known to have noticeable antitumor activity [16,17,18]. Their ability to act over the programmed cell death (apoptosis) and their influence on the damage of the DNA chain of the pathological cells were presented
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