Mol Pharm. 2009 Nov 3. [Epub ahead of print]

Partial Correction of Cystic Fibrosis Defects with PLGA Nanoparticles Encapsulating Curcumin.

Cartiera MS, Ferreira EC, Caputo C, Egan ME, Caplan MJ, Saltzman WM.

Cystic fibrosis (CF) is a common life threatening genetic disease (incidence: ~1 in 2500 live births). CF is caused by mutations in CFTR, a chloride channel involved in epithelial secretion of fluid and electrolytes. The most common mutation entails the deletion of a phenylalanine in position 508 that causes protein misfolding and abnormal CFTR processing. The DeltaF508 mutation accounts for approximately 70% of all CF alleles and about 90% of CF patients carry at least one copy of DeltaF508 CFTR.

Curcumin, a natural constituent of Curcuma Longa (turmeric spice), is a non-toxic low-affinity SERCA (Sarco (Endo)plasmic Reticulum Calcium ATPase) pump inhibitor thought to permit DeltaF508 CFTR escape from the ER. The compound has been shown to be capable of correcting the defect in cell lines and mice expressing F508 CFTR. In this work, poly-lactic-co-glycolic acid (PLGA) nanoparticles encapsulating curcumin were synthesized and used to treat two different CF mouse strains in an effort to correct the defects associated with CF by improving bioavailability of the compound, which has previously been a challenge in treatment with curcumin.

Our results suggest that oral administration of PLGA nanoparticles encapsulating curcumin enhances the effects of curcumin therapy in CF mice, as compared to delivery of non-encapsulated curcumin.

PMID: 19886674 [PubMed - as supplied by publisher]

Curcumin cross-links cystic fibrosis transmembrane conductance regulator (CFTR) polypeptides and potentiates CFTR channel activity by distinct mechani

J Biol Chem. 2009 Sep 9. [Epub ahead of print]

Curcumin cross-links cystic fibrosis transmembrane conductance regulator (CFTR) polypeptides and potentiates CFTR channel activity by distinct mechanisms.

Bernard K, Wang W, Narlawar R, Schmidt B, Kirk KL.

University of Alabama at Birmingham, United States;

Cystic fibrosis (CF) is caused by loss-of-function mutations in the CFTR chloride channel. Wild type and mutant CFTR channels can be activated by curcumin, a well tolerated dietary compound with some appeal as a prospective CF therapeutic. However, we show here that curcumin has the unexpected effect of cross-linking CFTR polypeptides into SDS-resistant oligomers. This effect occurred for CFTR channels in microsomes as well as in intact cells and at the same concentrations that are effective for promoting CFTR channel activity (5-50 microM).

Both mature CFTR polypeptides at the cell surface and immature CFTR protein in the endoplasmic reticulum were cross-linked by curcumin, although the latter pool was more susceptible to this modification. Curcumin cross-linked two CF mutant channels (deltaF508 and G551D) as well as a variety of deletion constructs that lack the major cytoplasmic domains. In vitro cross-linking could be prevented by high concentrations of oxidant scavengers (i.e., reduced glutathione and sodium azide) indicating a possible oxidation reaction with the CFTR polypeptide. Importantly, cyclic derivatives of curcumin that lack the reactive beta- diketone moiety had no cross-linking activity. One of these cyclic derivatives stimulated the activities of wild type CFTR channels, 1198-CFTR channels and G551D-CFTR channels in excised membrane patches. Like the parent compound, the cyclic derivative irreversibly activated CFTR channels in excised patches during prolonged exposure (> 5 min).

Our results raise a note of caution about undesired biochemical effects of reactive compounds like curcumin in the treatment of CF. Cyclic curcumin derivatives may have better therapeutic potential in this regard.

PMID: 19740743 [PubMed - as supplied by publisher]

FULL ARTICLE http://www.jbc.org/cgi/reprint/M109.056010v1.pdf