Letter to the Editor pubs.acs.org/acsmedchemlett
Curcumin May Defy Medicinal Chemists
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recent review by Nelson et al.1 published in Journal of Medicinal Chemistry has concluded that curcumin does not satisfy any of the tenets of medicinal chemistry properties to qualify as a drug for any application. It has been pointed out that most of the results based on in vitro studies in cell lines are not reliable due to the interference in assay readouts, and in vivo and clinical study results are “much ado about nothing”. Curcumin is classified under PAINS (pans-assay interference compounds) and IMPs (invalid metabolic panaceas), and curcumin analogues for improved delivery systems are disregarded as “based on a fairly weak foundation”. A few other natural products listed under this category are ginsenosides, genistein, quercetin, apigenin, nordihydroguaiaretic acid, resveratrol, kaempferol, and fistein. With over 10,000 papers published and 120 clinical trials under various stages of progress using curcumin, the review is a huge dampener, considering the projected potential of curcumin and other natural products as a panacea. Even if 1% of the papers published make sense, it would still be a sizable number to warrant against passing a negative verdict on the whole field. The review has picked four clinical trials and concluded that given its low systemic bioavailability, it is doubtful whether oral curcumin would ever be effective in human clinical trials. It is also possible to pick examples where a significant beneficial effect is seen. In a randomized, registered, clinical trial with 45 rheumatoid arthritis patients, it was shown that curcumin formulation is superior to diclofenac sodium or even a combination in terms of a significant reduction in primary and secondary end points based on DAS (disease activity score) and ACR (American College of Rheumatology) criteria.2 In another registered trial with chronic obstructive pulmonary disease (COPD), mainly caused by smoking and leading to coronary artery disease, theracurcumin, a highly absorbable formulation of curcumin, was shown to cause a significant decrease in AT-LDL (α1antitrypsin-low-density lipoprotein) in blood over placebo. The data obtained from 39 patients over a 6-month period warrants long-term study with cardiovascular events as primary end points.3 In terms of mechanisms involved, curcumin may act through mechanisms that are not addressed in the review.1 As an example, we would like to quote our studies on experimental malaria with P. berghei-infected mice. In a parasite recrudescence model created using suboptimal dose of arteether (single i.m. injection), the animals died between 22 and 25 days, while the infected mice without drug treatment died between 7 and 8 days. Three oral doses of native curcumin (Sigma-Aldrich) in DMSO (5 mg/mouse/day) given along with single injection of arteether prevented parasite recrudescence and almost completely protected the animals against mortality. Data from around 200 mice collected over a 4-year period indicated 95% survival in curcumin-treated animals compared to appropriate controls, where the survival was only 3−5%. Interestingly, curcumin treated animals had a high level of antiparasite antibodies at the time of recrudescence. In another experiment with the experimental cerebral malaria (ECM) model in mice, three oral doses of native curcumin in DMSO prevented © XXXX American Chemical Society
neurological symptoms and delayed the death. The animals died due to anemia and not because of cerebral malaria. Curcumin prevented the breakdown of blood−brain barrier and sequestration of infected RBCs in brain, and inhibited biochemical parameters of inflammation. Curcumin was detected transiently in plasma, not exceeding 10 ng/mL after a single oral dose. All these original publications are cited in our Forum article, where we have proposed clinical trials with curcumin as an adjunct drug in a few infectious diseases, including cerebral malaria.4 The positive effect of curcumin, long after it has disappeared from circulation, would suggest some kind of an immune memory effect. Thus, circulatory levels of curcumin in the plasma do not seem to be relevant in the case of curcumin, which appears to act through mechanisms beyond the well-accepted tenets of medicinal chemistry. While a cautionary approach is welcome, summary dismissal of an entire area of research is like throwing the baby out with bath water.
Govindarajan Padmanaban*,† Viswanathan A. Nagaraj‡ †
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Department of Biochemistry, Indian Institute of Science, Bangalore-560012, India ‡ Infectious Disease Biology, Institute of Life Sciences, Bhubaneswar-751023, India
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Phone: +91 80 23601492. Notes
Views expressed in this letter are those of the authors and not necessarily the views of the ACS.
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REFERENCES
(1) Nelson, K. M.; Dahlin, J. L.; Bisson, J.; Graham, J.; Pauli, G. F.; Walters, M. A. The essential medicinal chemistry of curcumin. J. Med. Chem. 2017, DOI: 10.1021/acs.jmedchem.6b00975. (2) Chandran, B.; Goel, A. A randomized, pilot study to assess the efficacy and safety of curcumin in patients with active rheumatoid arthritis. Phytother. Res. 2012, 26, 1719−1725. (3) Funamoto, M.; Sunagawa, Y.; Katanasaka, Y.; Miyazaki, Y.; Imaizumi, A.; Kakeya, H.; Yamakage, H.; Satoh-Asahara, N.; Komiyama, M.; Wada, H.; Hasegawa, K.; Morimoto, T. Highly absorptive curcumin reduces serum atherosclerotic low-density lipoprotein levels in patients with mild COPD. Int. J. Chronic Obstruct. Pulm. Dis. 2016, 11, 2029−2034. (4) Padmanaban, G.; Rangarajan, P. N. Curcumin as an adjunct drug for infectious diseases. Trends Pharmacol. Sci. 2016, 37, 1−3.
Received: February 6, 2017 Accepted: February 9, 2017
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DOI: 10.1021/acsmedchemlett.7b00051 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
