Affiliation:
1. Aarhus University Hospital (AUH)
2. Hammel Neurorehabilitation Centre and University Research Clinic
3. Aarhus University (AU)
Abstract
Abstract
Hypoxia-activated pro-drugs like TH-302 have failed clinically, possible due to variable activity of drug-activating reductases. Here we compared TH-302 and the natural product BE-43547, that targets hypoxic cells independently of reductases. Tumor cells in monolayers were treated with BE-43547 for 4 or 24h while exposed to different oxygenation regimes, and hypoxia-cytotoxicity-ratios (HCR) were quantified from dose-response curves. For comparison, selected experiments were repeated for TH-302. Finally, both drugs were tested in spheroids exposed to 20%/0% O2 for 24h. BE-43547 displayed strongly enhanced, cell line-independent, cytotoxicity under anoxia with HCR’s of ~ 100 following 24h treatment. HCR dropped to ~ 20 at 0.5% O2. HCR remained above 40 even when treatment time was reduced to 4h. Hypoxia selectivity was excellent regardless of whether drug was added prior to or during the hypoxic challenge. In comparison, HCR’s for TH-302 were lower with considerable variability across cell lines. BE-43547 and TH-302 were both unable to fully sterilize anoxic incubated spheroids. BE-43547 is highly hypoxia-selective, and, unlike TH-302, displayed minimal variability between cell lines, suggesting that BE-43547 targets a fundamental feature/target that is only present, or of survival importance, during hypoxia. Spheroid experiments suggests inadequate tissue penetrability, which may be overcome by designing novel drug analogues.
Publisher
Research Square Platform LLC
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