Henke_1final.QXP
11/12/08
4:21 pm
Page 76
Cystic Fibrosis
Bench to Bedside for Curcuma longa L in Cystic Fibrosis—
Curcumin’s Controversial Role as Therapy
a report by
D a v i d C H e n ke , M D , M P H
Associate Professor of Medicine, University of North Carolina at Chapel Hill
Cystic fibrosis (CF) affects several organ systems including the respiratory and
digestive systems.1 Usually, respiratory failure associated with mucoidy
Pseudomonas aeruginosa infection causes death.1 Most often, CF is linked to
a phenylalanine 508 deletion (∆F508 CFTR) in the cystic fibrosis
transmembrane conductance regulator (CFTR), an anion-selective channel in
the cell’s apical membrane.1 Its intracellular trafficking depends on interactions
with macromolecular complexes that target CFTR’s delivery to the apical
membrane.2–4 ∆F508 CFTR is functional5–7 but not protective because too little
reaches the apical surface.8–10 However, a well phenotype requires only 5–30%
CFTR function.11–14 Demonstrating enhanced ∆F508 CFTR function in cells
grown at low temperature suggests that therapies that increase CFTR function
in CF can be developed.7 The yellow spice curcumin (45mg/kg/day orally) in
the root of Curcuma longa L has shown therapeutic promise by this
mechanism in a ∆F508 CF mouse.8 Emanuele et al.15 have proposed three
mechanisms whereby curcumin may influence CF pathophysiology. They
suggest that it may directly activate CFTR, promote CFTR trafficking to the
apical membrane, and control pathological airway inflammation.15
Objective
The objective of this investigation was to assess the efficacy of oral curcumin
in CF at a dose that is safe for humans (8gm/day orally)16–18 and comparable
to the effective dose in the CF mouse (45mg/kg/day orally).8
Case Reports
The subject of case study 1 was a 45-year-old, 62-inch tall, ~52kg (body mass
index [BMI] ~21) female with homozygous ∆F508 CFTR, mucoidy P.
aeruginosa airway disease, and pancreatic insufficiency with abdominal
symptoms refractory to enzyme replacement maintained on airway clearance
therapy, Advair, oral azithromycin, fat-soluble vitamins, a high-protein diet,
and an exercise program. She declined supplemental oxygen therapy.
Prophylactic inhaled antibiotics, DNAase, and hypertonic saline were poorly
tolerated or ineffective.
This subject had required more intravenous (IV) antibiotics to manage
increasingly frequent CF exacerbations (see Figure 1) until starting curcumin.
David C Henke, MD, MPH, is an Associate Professor of Medicine
in the Division of Pulmonary and Critical Care Medicine at the
University of North Carolina at Chapel Hill. His research interest
focuses on understanding the influence of the host inflammatory
response on chronic disease states. He holds boards in internal
medicine, pulmonary medicine, critical care, and dermatology.
E: [email protected]
76
A typical exacerbation in spring 2003 documented an arterial hemoglobin
oxygen saturation (AHOS) of 80% at rest by patient home monitoring,
profound lethargy, increased sputum, frank hemoptysis, and dyspnea that
prohibited exercise and working. On March 7, 2003 her AHOS dropped to
71% during a six-minute walk test in the clinic (fraction of inspired oxygen
[FiO2] 21%, 1,820 feet). After IV antibiotics her active lifestyle returned and
during a clinic visit on March 13, 2003 she maintained an AHOS of 97% (FiO2
21%, 1,800 feet) during a six-minute walk test. However, her symptoms
returned after a few weeks and she received another course of IV antibiotics.
Her serum albumin declined to 2.1G/dl (normal 3.5–5) in July 2003. During
2003, she required 104 days of antibiotics (see Figure 1).
Following a spring 2004 exacerbation, she was again treated with IV
antibiotics that were poorly tolerated. As IV antibiotics were increasingly
associated with only transient improvement, she requested that an alternative
to IV antibiotics be used to treat rapidly developing symptoms during summer
2004. She also stopped taking pancreatic enzyme supplements, which had
never corrected her abdominal symptoms. In July 2004 she began orally
ingesting curcumin 3.6gm/day to address worsening CF symptoms that
included AHOS dropping to 80% as measured by home monitoring. She
obtained curcumin from an Asian market, weighed it on a scale, and ingested
it orally as a powder. In November 2004 she reported improved sputum, the
resolution of hemoptysis, and an AHOS above 88% with exercise. She
stopped curcumin twice because its use was not supported by some
physicians. On both occasions her symptoms returned, but resolved without
IV antibiotics after re-starting curcumin. She increased the dose to 8gm/day
because it was well tolerated.
Pulmonary function testing (PFT) was performed sporadically and only on 10
occasions during this period due to patient discomfort performing them.
However, available studies demonstrate a forced expiratory volume in one
second (FEV1) of 1.42l/second (52%) during an exacerbation while transiently
not taking curcumin in October 2005. When she recovered without IV
antibiotics after re-starting curcumin, her FEV1 returned to 1.65l/second
(60%) in March 2006, a result comparable with her ‘well‘ baseline. There are
no six-minute walk test results from this period. However, patient home
monitoring supports a correlation between curcumin use and maintaining an
AHOS above 88% during exercise. While taking curcumin, her albumin
increased from 2.1G/dl to a normal level of 4.2G/dl (3.5–5.0G/dl) on June 7,
2006. Concentrations of fat-soluble vitamin E of 11.1mg/l (5.5–17) and 1,25
vitamin D of 37pg/ml (22–67) were normal, while the concentration of
vitamin A was low at 171ug/l (360–1,200) while taking curcumin on 8
December, 2006 (pre-curcumin levels are unavailable for the vitamins; stool
fat analysis was declined by the patient). Her refractory abdominal cramps and
© TOUCH BRIEFINGS 2008
Henke_1final.QXP
11/12/08
4:22 pm
Page 77
Bench to Bedside for Curcuma longa L in Cystic Fibrosis—Curcumin’s Controversial Role as Therapy
The subject of case study 2 was a 41-year-old, 72-inch tall, 70kg (BMI 22)
male with ∆F508/G1061R CFTR mutations, chronic airway infection with
mucoidy P. aeruginosa, pancreatic insufficiency, an FEV1 ~1.21l/second (28%),
and frequent life-threatening hemoptysis associated with low serum level of
von Willebrand factor that corrected with desmopressin (DDAVP). He was
maintained on Advair, prophylactic oral antibiotics, pancreatic enzymes, fatsoluble vitamin supplements, a high-protein diet, and an exercise program.
Prophylactic inhaled antibiotics, DNAase, and hypertonic saline have been
avoided, and PFTs were rarely performed due to concerns that they may
aggravate hemoptysis. He declined supplemental oxygen and six-minute walk
testing. He reported noticeably improved exercise tolerance and sputum
production taking 8gm/day of 95% root curcumin orally (beginning in fall
2004). These symptoms worsened when he stopped taking the product.
Unlike the first patient, his gastrointestinal symptoms were controlled by
pancreatic enzyme supplements, which he continued taking. Taking
pancreatic enzyme supplements and curcumin, the concentrations of vitamin
E of 10.6mg/l (5.5–17) and total vitamin D of 28ng/ml (25–80) were normal.
However, as with the first patient on curcumin and no pancreatic enzyme
supplement, the concentration of vitamin A of 271ug/l (360–1,200) was low
when it was measured on January 19, 2007. Vitamin levels before beginning
curcumin are unavailable and this patient also declined stool-fat analysis. He
was now compliant with taking curcumin because he considered it to be an
effective part of his prophylactic CF management.
Our first patient with homozygous ∆F508 CFTR reports that “the addition of
the curcumin… put me back on the road to recovery.” Our second patient
states that “curcumin has proven to aid in airway clearance… I notice a
definite improvement when taking it.” Currently, both patients are extremely
compliant with taking curcumin because they believe it improves their CF
symptoms and significantly enhances their quality of life. Neither patient has
noted adverse effects during the three years of taking curcumin 3.6–8gm/day.
Results
CF symptoms decreased with the use of curcumin in both patients. Dyspnea,
hemoptysis, refractory abdominal symptoms, and the need for IV antibiotics
markedly improved in the patient with homozygous ∆F508 CFTR. The
objective improvement in this patient is most readily demonstrated by
avoiding the need for IV antibiotics for 792 days while taking curcumin orally
after requiring 104 days of IV antibiotics the year before. No adverse effects
were reported by either patient taking curcumin 3.6–8gm/day for three
years. Curcumin root appears to contain the active compound because
curcumin products without it did not control CF symptoms.
Discussion
Egan’s report that curcumin prolonged survival and corrected the ion transport
defect in respiratory and intestinal epithelia in a homozygous ∆F508 CFTR
mouse8 is supported by other investigators.9,10,19,20–23 These reports appear
US RESPIRATORY DISEASE
Figure 1: Curcumin Halted the Accelerating Need for Intravenous
Antibiotics in a Patient with ∆F508 CFTR Cystic Fibrosis
110
100
90
80
Days of IV antibiotics per year
light-colored, greasy, floating stools resolved without pancreatic enzyme
replacement after starting curcumin. The cyanosis and clubbing of her digits
also noticeably improved. No antibiotics were required between May 4, 2004
and July 6, 2006 (792 days) while taking curcumin. Symptoms returned in
summer 2006, when she changed to a curcumin product containing no root.
Her FEV1 fell to 1.23l/second (45%) on September 5, 2006. She clinically
improved and her FEV1 rose to 1.51l/second (56%) on November 7, 2006
after receiving IV antibiotics and re-starting a 95% root curcumin product.
Curcumin
70
60
792 days off IV
antibiotics
50
40
30
20
10
0
1998
1999
2000
2001
2002
2003
2004
2005
2006
Year
This figure tracks the requirement for intravenous (IV) antibiotics per year in a female
homozygous ∆F508 CFTR cystic fibrosis (CF) patient between November 7, 2006 and January 1,
1998. It demonstrates an accelerated use of IV antibiotics as her clinical condition deteriorated
until she started curcumin in August 2004. In 2003, she received 104 days of IV antibiotics. Early
in 2004 she required another 28 days of IV antibiotics. This rapid deterioration suggested the
continued need for large amounts of IV antibiotics during 2004. However, because IV antibiotics
were increasingly less effective and poorly tolerated secondary to allergic reactions, nausea, poor
appetite, and transient weight loss, she requested to try an alternative therapy in the summer of
2004 to manage her worsening symptoms. She began taking curcumin in August 2004 and her
CF symptoms improved. She did not need IV antibiotics for 729 days until July 2006, when she
again clinically worsened and agreed to receive IV antibiotics. This exacerbation was associated
with a change in the source of curcumin (necessitated by the business closing) from an Asian
market powder to a now discontinued preparation obtained from a health food store that
contained no curcumin root.
plausible given the modest CFTR function needed to produce a well
phenotype11–14 and the clinical experience reported in these cases. Curcumin is
the most effective intervention for CF ever tested in the homozygous ∆F508
patient described in this report based on her not requiring IV antibiotics for 792
days (after requiring 104 days of IV antibiotics the prior year [see Figure 1]) and
the resolution of her life-long refractory abdominal complaints. The second
patient described herein with different mutations and a lower FEV1 also
significantly benefited from curcumin, but his improvement was mainly
subjective. The case for curcumin is made stronger since cessation in both
patients was associated with the worsening of CF symptoms. The active
ingredient appears to be concentrated or present only in the curcumin root, as
the product used by the first patient without it did not control her symptoms.
However, other investigators do not support Egan.24–27 These conflicting
observations have been speculatively attributed to differences in the genetic
background in the mouse models.15,23 Other possibilities include differences in
curcumin dosing, duration of treatment, source, preparation, and storage.
Conflicting reports, different clinical response in these patients with different
CF mutations and pulmonary function, and the variable efficacy associated
with curcumin from different sources highlight the need for further studies and
controlled clinical trials.
Conclusion
These cases support the implication in Egan’s report that curcumin may be
a novel and urgently needed therapy for CF. However, curcumin’s active
77
Henke_1final.QXP
11/12/08
4:22 pm
Page 78
Cystic Fibrosis
component must be identified and the results of prospective controlled
clinical trails in well-characterized CF patients must be published before it
can be recommended. ■
Rowe S, Miller S, Sorscher E, et al., Cystic Fibrosis, N Engl J Med,
2005;352:1992–2001.
2. Ameen N, Silvis M, Bradbury N, et al., Endocytic trafficking of
CFTR in health and disease, J Cystic Fibrosis, 2007;6:1–14.
3. Riodan R, Assembly of Functional CFTR Chloride Channels, Ann
Rev Physiol, 2005;67:701–18.
4. Sadlish H, Skach WR, Biogenesis of CFTR and other Polytopic
Membrane Proteins: New Roles for the Ribosome-Translocon
Complex, J Membrane Biol, 2004;202:115–26.
5. Kopito RR, Biosynthesis and Degradation of CFTR, Physiol Rev,
1999;79(Suppl. 1):167–73.
6. Welsh MJ, Ramsey BW, Accurso F, Cutting GR, Cystic Fibrosis. In:
Scriver CR, Beaudet AL, Sly WS, et al. (eds), The Metabolic and
Molecular Basie of Inherited Disease, Eighth Edition, New York:
McGraw-Hill Inc., 2001;5121–89.
7. Denning GM, Anderson MP, Amara JP, et al., Processing of mutant
cystic fibrosis transmembrane conductance regulator is
temperature-sensitive, Nature, 1992;358:761–4.
8. Egan ME, Pearson M, Weiner SA, et al., Curcumin, a Major
Constituent of Turmeric, Corrects Cystic Fibrosis Defects, Science,
2004;304(5670):600–602.
9. Berger AL, Randak CO, Ostedgaard LS, et al., Curcumin stimulates
cystic fibrosis transmembrane conductance regulator CI-channel
activity, J Biol Chem, 2005;280(7):5221–6.
10. Wang W, Li G, Clancy JP, Kirk KL, Activating Cystic Fibrosis
Transmembrane Conductance Regulator Channels with Pore
Blocker Analogs, J Biol Chem, 2005;280(25):23622–30.
11. Davis J, et al., Cystic Fibrosis, Am J Crit Care Med, 1996;154:
1.
Acknowledgment
The author would like to thank Mr Nicholas Boyd for his secretarial
assistance preparing this manuscript.
1329–1996.
12. McKone E, Emerson SS, Edward KL, et al., Effect of genotype on
phenotype and mortality in cystic fibrosis: retrospective cohort
study, Lancet, 2003;361:1671–6.
13. Noone PG, Pue CA, Zhaoqing Z, et al., Lung disease associated
with the IVS8 5T allele of the CFTR gene, Am J Respir Crit Care
Med, 2000;162:1919–24.
14. Noone PG, Zhou A, Silverman LM, et al., Cystic fibrosis gene
mutation and pancreatitis risk: relation to epithelial ion transport
and trypsin inhibitor gene mutations, Gastroenterology,
2001;121:1310–19.
15. Emanuele E, et al., Potenial usefulness of curcumin in cystic
fibrosis, Medical Hypotheses, 2007;69:222–3.
16. Cheng AL, Hsu CH, Liu JK, et al., Phase I clinical trial of curcumin,
a Chemopreventive agent, in patients with high-risk or premalignant lesions, Anticancer Res, 2001;21:2895–2900.
17. Sharma RA, McLelland HR, Hill KA, et al., Pharmacodynamic and
pharmacokinetic study of oral Curcmin extract in patients. With
colorectal cancer, Clin Cancer Res, 2001;7:1894–1900.
18. Lao CD, Ruffin MT, Normolle D, et al., Dose escalation of a
curcuminoid formulation, BMC Complement Altern Med, 2006;6.
19. Lipecka J, Norez C, Bensalum N, et al., Rescue of ∆F508-CFTR
(Cystic Fibrosis Transmembrane Conductance Regulator) by
Curcumin: Involvement of the Keratin 18 Network,
J Pharmacology Exp Ther, 2006;10:1124/105.097667.
20. Van Goor F, Straley KS, Cao D, et al., Rescue of ∆F508-CFTR
trafficking and gating in human cystic fibrosis airway primary
cultures by small molecules, Am J Physiol Lung Cell Mol Physiol,
2006;290:L1117–30.
21. Davezac N, Tondelier D, Lipecka J, et al., Global proteomic
approach unmasks involvement of keratins 8 and 18 in the
Delivery of cystic fibrosis transmembrane conduclance regulator
(DFTR/delta ∆F508-CFTR to plasma membrane), Proteomics,
2004;4(12):3833–44.
22. Norez C Antigny F, Becq F, Vandebrouck C, et al., Maintaining low
Ca2+Level in the Endoplasmic Reticulum Restores Abnormal
Endogenous ∆F508del-CFTR Trafficking in Airway Epithelial Cells,
Traffic, 2006;(5):562–73.
23. Lu M, Leng Q, Egan ME, et al., CFTR is required for
PKA-regulated ATP sensitivity of Kir1.1 potassium channels in
mouse kidney, J Clin Investigation, 2006;116:797–807.
24. Grubb BR, Gabriel SE, Mengos A, et al., SERCA Pump Inhibitors
Do Not Correct Biosynthetic Arrest of ∆F508-CFTR in Cystic
Fibrosis, Am J Resp Cell and Mole Bio, 2006;(34):355–63.
25. Dragomir A, Bjorstad J, Hjelte L, Roomans GM, Curcumin does not
stimulate cAMP-mediated chloride transport in cystic fibrosis
airway epithelial cells, Biochem Biophys Res Commun,
2004;322:447–51.
26. Song Y, Sonawan ND, Salinas D, et al., Evidence against the
Rescue of Defective ∆F508-CFTR Cellular Processing by Curcumin
in Cell Culture and Mouse Models, Biol Chem,
2004;279:40629–40633.
27. Loo T, Bartlett C, Clarke DM, Thapsigargin or curcumin does not
promote maturation of processing mutants of the ABC
transporters, CFTR, and F-glycoprotein, Biochem Biophysical Res
Comm, 2004;325:580–85.
E v e n t s D i a r y — C y s t i c F i b ro s i s
February 7, 2009
The Cystic Fibrosis Institute
Glenview, IL
www.cysticfibrosisinstitute.org
April 15–19, 2009
New Frontiers in Basic
Science of Cystic Fibrosis
Tavira, Portugal
www.ecfs.eu/tavira2009
July 31 – August 2, 2009
22nd National Cystic Fibrosis
Family Education Conference
Redwood City, CA
October 31 – November 5, 2009
American College of
Chest Physicians
San Diego, CA
www.cfri.org
www.chestnet.org/CHEST/program/about09.php
29 August – September 1, 2009
8th Australasian Cystic
Fibrosis Conference
Brisbane, Australia
May 26–29, 2010
5th International Primary
Care Respiratory Group
World Conference
Toronto, Canada
www.cysticfibrosis.org.au
May 15–20, 2009
American Thoracic Society
International Conference
San Diego, CA
www.thoracic.org
June 10–13, 2009
32nd European Cystic
Fibrosis Conference
Brest, France
www.ecfs.eu/brest2009
78
www.theipcrg.org
September 30 – October 3, 2009
American Association Cardiovascular
and Pulmonary Rehabilitation
24th Annual Meeting
Pittsburgh, PA
June 16–19, 2010
33rd European Cystic
Fibrosis Conference
Valencia, Spain
www.aacvpr.org/EventsEducation/AnnualMeeting
www.ecfs.eu/conferences
October 15–17, 2009
23rd Annual NACF Conference
Minneapolis, MN
October 20–22, 2010
23rd Annual NACF Conference
Baltimore, MD
www.nacfconference.org
www.nacfconference.org
US RESPIRATORY DISEASE