In Vitro Characterization of the Bacteria-derived Hypoxia-selective Cytotoxin BE-43547

Morten Busk*, Peter P Eggertsen, Jens Overgaard, Michael R Horsman, Thomas Tørring, Kristian M Jacobsen, Thomas B Poulsen

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

Abstract

BACKGROUND/AIM: Hypoxia-activated pro-drugs, such as TH-302, may kill hypoxic treatment-resistant tumor cells, but have failed in clinical trials. This may be related to variable levels of drug-activating reductases. Compounds such as bacteria-derived BE-43547, which target hypoxic cells independently of reductases, may be beneficial. This study characterized the in vitro potency and hypoxia selectivity of BE-43547 and TH-302.

MATERIALS AND METHODS: Tumor cells were exposed to different oxygenation levels in the presence/absence of drug, and survival was quantified using total cell number (BE-43547) or clonogenic survival (BE-43547 and TH-302) assays. Half-maximal inhibitory concentration (IC 50) values and the hypoxia-cytotoxicity-ratio (HCR: normoxic IC 50/hypoxic IC 50) were determined from dose-response curves. Finally, both drugs were tested in spheroids exposed to 20% or 0% O 2 for 24 h followed by assessment of clonogenic survival.

RESULTS: BE-43547 was highly potent and displayed little inter-cell line variability. Strongly enhanced cytotoxicity was observed under oxygen-restricted conditions with HCR's of ~100 and ~20 after 24 h of treatment with 0 or 0.5% O 2, respectively. Reducing treatment time somewhat reduced hypoxia selectivity. Hypoxia selectivity was observed regardless of whether the drug was added before or during the hypoxic challenge. TH-302 IC 50 values varied 10-fold under oxic conditions, whereas those of the anoxic-to-normoxic HCR varied from 15 to 88. Both BE-43547 and TH-302 were unable to completely sterilize anoxic incubated spheroids.

CONCLUSION: 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 suggested inadequate tissue penetrability, which may be overcome by designing novel drug analogs.

OriginalsprogEngelsk
TidsskriftAnticancer Research
Vol/bind43
Nummer12
Sider (fra-til)5319-5329
Antal sider11
ISSN0250-7005
DOI
StatusUdgivet - dec. 2023

Fingeraftryk

Dyk ned i forskningsemnerne om 'In Vitro Characterization of the Bacteria-derived Hypoxia-selective Cytotoxin BE-43547'. Sammen danner de et unikt fingeraftryk.

Citationsformater