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Am J Physiol Lung Cell Mol Physiol (March 21, 2003). doi:10.1152/ajplung.00351.2002
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Submitted on October 21, 2002
Accepted on March 12, 2003

CFTR activation in human bronchial epithelial cells by novel benzoflavone and benzimidazolone compounds

Emanuela Caci1, Chiara Folli1, Olga Zegarra-Moran1, Tonghui Ma2, Mark F. Springsteel3, Robert E. Sammelson3, Michael H. Nantz3, Mark J. Kurth3, Alan S. Verkman2, and Luis J. Galietta1*

1 Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, Genova, Italy
2 Department of Medicine and Physiology, University of California San Francisco, San Francisco, USA
3 Department of Chemistry, University of California Davis, Davis, USA

* To whom correspondence should be addressed. E-mail: galietta{at}unige.it.

Activators of the CFTR Cl- channel may be useful for therapy of cystic fibrosis. Short-circuit current (Isc) measurements were done on human bronchial epithelial cells to characterize the best flavone and benzimidazolone CFTR activators identified by lead-based combinatorial synthesis and high-throughput screening. The 7,8-benzoflavone UCCF-029 was a potent activator of Cl- transport, with activating potency (<1 µM) being much better than other flavones such as apigenin. The benzimidazolone UCCF-853 gave similar Isc but with lower potency (5-20 µM). In combination, the effect induced by maximal UCCF-029 and UCCF-853 was 50-80% greater than that of either compound alone. The apparent activating potencies (Kd) of UCCF-029, UCCF-853 and apigenin increased strongly with increasing basal CFTR activity: for example, Kd for activation by UCCF-029 decreased from > 5 µM to < 0.4 µM with increasing basal Isc from ~=4 µA/cm2 to ~=12 µA/cm2. This dependence was confirmed in permeabilized Fischer rat thyroid (FRT) cells stably expressing CFTR. Our results demonstrate efficacy of novel CFTR activators in bronchial epithelia and provide evidence that activating potency depends on basal CFTR activity.




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