An ex vivo perfused ventilated murine lung model suggests lack of acute pulmonary toxicity of the potential novel anticancer agent (-)-englerin A
- PMID: 35165752
- PMCID: PMC8921049
- DOI: 10.1007/s00204-022-03235-z
An ex vivo perfused ventilated murine lung model suggests lack of acute pulmonary toxicity of the potential novel anticancer agent (-)-englerin A
Abstract
(-)-Englerin A (EA), a potential novel anti-cancer drug, is a potent selective activator of classical transient receptor potential 4 and 5 (TRPC4, TRPC5) channels. As TRPC4 channels are expressed and functional in the lung endothelium, possible side effects such as lung edema formation may arise during its administration. Well-established in vivo rodent models for toxicological testing, however, rapidly degrade this compound to its inactive derivative, englerin B. Therefore, we chose an ex vivo isolated perfused and ventilated murine lung (IPVML) model to detect edema formation due to toxicants, which also reduces the number of incriminating animal experiments required. To evaluate the sensitivity of the IPVML model, short-time (10 min) drops of the pH from 7.4 down to 4.0 were applied, which resulted in linear changes of tidal volumes, wet-to-dry weight ratios and incorporation of FITC-coupled dextran particles from the perfusate. As expected, biological activity of EA was preserved after perfusion in the IPVML model. Concentrations of 50-100 nM EA continuously perfused through the IPVML model did not change tidal volumes and lung weights significantly. Wet-to-dry weight ratios were increased after perfusion of 100 nM EA but permeation of FITC-coupled dextran particles from the perfusate to the lung tissues was not significantly different. Therefore, EA shows little or no significant acute pulmonary toxicity after application of doses expected to activate target ion channels and the IPVML is a sensitive powerful ex vivo model for evaluating acute lung toxicity in accordance with the 3R rules for animal experimentation.
Keywords: Anti-cancer drug; Classical transient receptor potential 4 and 5 (TRPC4, TRPC5); FITC–dextran permeation assay; Lung edema; Tidal volume; Wet-to-dry weight ratio.
© 2022. The Author(s).
Conflict of interest statement
David Beech is an inventor on a patent to develop EA analogues as anti-cancer therapeutics: U.S. Patent No. 11,098,054 issued August 24, 2021. This patent can remain in force until July 5, 2038. Compounds for Treating Cancer. Inventors: John Beutler, Antonio Echavarren, William Chain, David Beech, Zhenhua Wu, Jean-Simon Suppo, Fernando Bravo, Hussein Rubaiy.The other authors declare no conflict of interest.
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