. Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects. Science. 2004 Apr 23;304(5670):600-2. PubMed.


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  1. Curcumin and Protein Misfolding
    The most common cause of cystic fibrosis is the δF508 mutation that causes ER misfolding and retention/degradation of the cystic fibrosis transmembrane conductance regulator (CFTR). This leads to a temperature-dependent failure of normal surface expression and chloride channel function. This new study reports that oral administration of non-toxic doses of curcumin by gavage (15 mg/kG body weight three times daily for three days) to transgenic mice expressing the mutant δF508CFTR corrects chloride channel function in nasal epithelia and rectal mucosa. Control studies show curcumin fails to correct for the loss of CFTR function in CFTR null mice, arguing for a CFTR-dependent mechanism. In vitro studies demonstrate that curcumin treatment partially corrects the temperature-dependent δF508 CFTR defects in ER accumulation, surface expression, channel function and retention in the ER bound to the calcium-dependent chaperone, calnexin. The authors attribute the corrective effects of curcumin to inhibition of the sarcoplasmic/endoplasmic reticulum calcium pump (SERCA), consistent with their earlier data showing that SERCA inhibitors in vitro allow functional maturation of CFTR. They suggest that curcumin or its derivatives may be used to treat cystic fibrosis.

    This paper shows that oral curcumin or a metabolite is sufficiently bioavailable with acceptable dosing to modulate the cystic fibrosis phenotype in vivo. This demonstration of a correction of in-vivo defects in chloride channel function directly related to the human disease phenotype by a drug with a favorable side-effect profile represents a very significant advance.

    How curcumin produces the in-vivo effect is not entirely resolved. Curcumin is a "dirty drug" with many potential targets, escalating with dose. Well-established low-dose effects begin around 0.1μM for inhibition of JNK activation of AP-1 transcription, potent antioxidant/ scavenger activity around 1 μM, with a plethora of enzyme inhibitory and anti-cancer activities described at 5μM and above. For example, a recent review (Aggarwal et al., 2003) lists downregulation of "transcription factors NF-κ B, AP-1 and Egr-1; downregulation of the expression of COX2, LOX, NOS, MMP-9, uPA, TNF, chemokines, cell surface adhesion molecules and cyclin D1; downregulation of growth factor receptors (such as EGFR and HER2); and inhibition of the activity of c-Jun N-terminal kinase, protein tyrosine kinases and protein serine/threonine kinases. "Among many other activities ascribed to curcumin, direct inhibition of SERCA at dosing between 5 and 15 μM can be listed. At high doses, for example, the 5 to 50μM doses used in the present in-vitro data, curcumin may have been acting as a SERCA inhibitor. However, due to efficient glucuronidation, in-vivo studies with high-dose, orally administered curcumin show peak plasma or serum levels at less than 2 μM and probably less than 0.5 μM at dosing comparable to what was used in the cystic fibrosis study. As Egan et al. note, specific SERCA inhibitors other than curcumin are toxic. In fact, there are many other high-dose, predictably toxic curcumin activities, and it seems highly likely that the limited bioavailability of curcumin is a key factor limiting its toxicity. Since the Egan et al. paper made no measurement of SERCA inhibition or ER calcium levels in vivo or in vitro, it is difficult to know whether SERCA activity was influenced at all beyond the GI tract with high curcumin exposure, for example, in nasal epithelia.

    This raises the issue of whether or not other curcumin activities related to protein misfolding may be responsible for correction of the cystic fibrosis defect. For example, curcumin may ameliorate the phosphorylation-dependent Cl- channel defect associated with the mutant CFTR (Wang et al., 2000). Alternatively, and perhaps relevant to neurodegenerative disease, curcumin may help correct the protein folding or conformation defect caused by deletion of Phe508 that results in destabilization of the α helix in that region of the nucleotide binding domain (NBD1-R) (Massiah et al., 1999). The δF508 mutation is in the NBD1 region of the CFTR, where circular dichroism analysis identifies 19 percent α helix and 43 percent β sheet and turn (Neville et al., 1998). Although misfolded CFTR does not accumulate as aggregates of β-pleated sheet, as do proteins accumulating in neurodegenerative diseases, it does show increased chaperone binding, retention, and a 10-fold reduction in maturation with surface expression. Curcumin resembles Congo red and binds to misfolded protease-resistant prions, preventing their aggregation at doses as low as 10 nm (Caughey et al., 2003). Similarly, our group has found that curcumin inhibits Aβ aggregation in vitro at submicromolar levels (Cole et al., 2003) and has a paper submitted expanding on these results in vivo. Clearly, inhibition of Aβ misfolding and aggregation could explain in-vivo data showing a reduction in aggregated Aβ accumulation in APP transgenics (see Lim et al., 2001 in ARF related news story) and Aβ-infused rats (Frautschy et al., 2001). Similarly, Takashima presented data at the Society for Neuroscience meetings showing that curcumin treatment reduced tau accumulation in transgenic mice bearing an FTD mutation. Because the prevention of prion, Aβ and possibly tau misfolding and accumulation occur at submicromolar doses that are achievable in vivo, researchers should consider alternative mechanisms to SERCA inhibition to explain the beneficial effects in the cystic fibrosis model. Whatever the mechanism, the significant phenotypic improvement in this model for a deadly incurable disease underscores the potential therapeutic promise for curcumin or related curcuminoid compounds in the clinic.


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