Can curcumin cure cystic fibrosis?

Cystic fibrosis, a progressive and ultimately fatal inherited disorder caused by a mutant cystic fibrosis transmembrane conductance regulator ( CFTR ) gene, has mobilized the government, charitable foundations, the biotechnology industry, and academia to work together to accelerate the development of drugs to combat the disease. The tools of molecular biology have facilitated the entry of about two dozen drugs in the developmental pipeline, any one of which, if successful, could halt the progression of the disease. As recently reported by Egan and colleagues, 1 the newest therapeutic candidate is curcumin, a so-called nutraceutical agent or dietary supplement that is a mixture of compounds derived from the curry spice turmeric. Curcumin has been on the shelves of health food stores for some time and has been touted as an antioxidant, antiviral, antiinflammatory, anticancer, and cholesterol-lowering herbal supplement. What led Egan et al. to study curcumin as a treatment for cystic fibrosis? They recognized that the most common cause of cystic fibrosis — the ∆ F508 mutation — results in a CFTR protein that is misprocessed in the endoplasmic reticulum; it is snagged by a chaperone protein and targeted for degradation, instead of making its way to the plasma membrane and forming a chloride channel. The absence of CFTR from the luminal-cell surface that lines the respiratory tract is associated with a deficit in chloride conductance regulated by cyclic AMP (cAMP) and a compensatory influx of sodium ions into the cell, with a consequent high sodium potential across the plasma membrane (Fig. 1). This promotes dehydration of the luminal environment and allows bacterial invasion and inflammation. Because some chaperone proteins are dependent on high calcium levels, the authors reasoned that reducing the calcium levels in the endoplasmic reticulum might liberate the mutant CFTR, increasing the odds of its reaching the cell surface (Fig. 1). They had previously shown that curcumin inhibits a calcium pump (called sarcoplasmic reticulum Ca-ATPase) in the endoplasmic reticulum and that, unlike some other inhibitors of this pump, curcumin has a low level of toxicity. Egan et al. administered curcumin by oral gavage to mice engineered to express only the ∆ F508 allele. 1 This mutant mouse expresses the cystic fibrosis defect primarily in the gastrointestinal tract and rarely lives beyond four weeks. Treated mice had dramatically increased rates of survival and normal cAMP-mediated chloride transport across the nasal and gastrointestinal epithelia. In addition, the transepithelial sodium potential was reduced, suggesting that sufficient ∆ F508 protein reached the plasma membrane. Although the authors hypothesized that reduced calcium levels in the endoplasmic reticulum would ameliorate the effects of the ∆ F508 mutation by interfering with the function of the chaperone protein, the mechanism through which