Evidence against the Rescue of Defective ΔF508-CFTR Cellular Processing by Curcumin in Cell Culture and Mouse Models

• Published in: The Journal of biological chemistry 2004-09, Vol.279 (39), p.40629-40633
• Main Authors: Song, Yuanlin, Sonawane, N.D., Salinas, Danieli, Qian, Liman, Pedemonte, Nicoletta, Galietta, Luis J.V., Verkman, A.S.
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M407308200

Curcumin, the yellow colored component of the spice turmeric, has been reported to rescue defective ΔF508-cystic fibrosis transmembrane conductance regulator (CFTR) cellular processing in homozygous mutant mice, restoring nasal potential differences and improving survival (Egan, M. E., Pearson, M., Weiner, S. A., Rajendran, V., Rubin, D., Glockner-Pagel, J., Canny, S., Du, K., Lukacs, G. L., and Caplan, M. J. (2004) Science 304, 600–602). Because of the implied potential use of curcumin or similar compounds in the therapy of cystic fibrosis caused by the ΔF508 mutation, we tried to reproduce and extend the pre-clinical data of Egan et al. Fluorometric measurements of iodide influx in Fischer rat thyroid cells expressing ΔF508-CFTR showed no effect of curcumin (1–40 μm) when added for up to 24 h prior to assay in cells grown at 37 °C. Controls, including 27 °C rescue and 4 mm phenylbutyrate at 37 °C, were strongly positive. Also, curcumin did not increase short circuit current in primary cultures of a human airway epithelium homozygous for ΔF508-CFTR with a 27 °C rescue-positive control. Nasal potential differences in mice were measured in response to topical perfusion with serial solutions containing amiloride, low Cl–, and forskolin. Robust low Cl– and forskolin-induced hyperpolarization of 22 ± 3 mV was found in wild type mice, with 2.1 ± 0.4 mV hyperpolarization in ΔF508 homozygous mutant mice. No significant increase in Cl–/forskolin hyperpolarization was seen in any of the 22 ΔF508 mice studied using different curcumin preparations and administration regimens, including that used by Egan et al. Assay of serum curcumin by ethyl acetate extraction followed by liquid chromatography/mass spectrometry indicated a maximum serum concentration of 60 nm, well below that of 5–15 μm, where cellular effects by sarcoplasmic/endoplasmic reticulum calcium pump inhibition are proposed to occur. Our results do not support further evaluation of curcumin for cystic fibrosis therapy.