The anti-inflammatory activity of curcumin is mediated by its oxidative metabolites

Abstract

The spice turmeric, with its active polyphenol curcumin, has been used as anti-inflammatory remedy in traditional Asian medicine for centuries. Many cellular targets of curcumin have been identified, but how such a wide range of targets can be affected by a single compound is unclear. Here, we identified curcumin as a pro-drug that requires oxidative activation into reactive metabolites to exert anti-inflammatory activities. Synthetic curcumin analogs that undergo oxidative transformation potently inhibited the pro-inflammatory transcription factor nuclear factor κB (NF-κB), whereas stable, non-oxidizable analogs were less active, with a correlation coefficient () of IC log of autoxidation rate of 0.75. Inhibition of glutathione biosynthesis, which protects cells from reactive metabolites, increased the potency of curcumin and decreased the amount of curcumin-glutathione adducts in cells. Oxidative metabolites of curcumin adducted to and inhibited the inhibitor of NF-κB kinase subunit β (IKKβ), an activating kinase upstream of NF-κB. An unstable, alkynyl-tagged curcumin analog yielded abundant adducts with cellular protein that were decreased by pretreatment with curcumin or an unstable analog but not by a stable analog. Bioactivation of curcumin occurred readily , which may explain the wide range of cellular targets, but if bioactivation is insufficient, it may also help explain the inconclusive results in human studies with curcumin so far. We conclude that the paradigm of metabolic bioactivation uncovered here should be considered for the evaluation and design of clinical trials of curcumin and other polyphenols of medicinal interest.

The mechanism(s) of action of antioxidants: From scavenging reactive oxygen/nitrogen species to redox signaling and the generation of bioactive secondary metabolites

“…However, by using an experimental setup that allowed in situ formation of the autoxidized products, Edwards et al found that NF‐κB inhibition by curcumin depends on oxidative activation, and that this is due to the reactive electrophile intermediates covalently binding to signaling proteins, such as for example IKKβ. Very interestingly, and in line with the perspective discussed here, they could clearly connect this activity to the oxidative status of the cells, in other words, they demonstrated that oxidative stress modulates curcumin's bioactivity through the in situ formation of oxidized intermediates …”

“…In their response, the authors disapproved this theory and presented evidence for the inactivity of 1za and 1zc for suppressing the activation of NF‐κB, in contrast with the case of curcumin . While the clinical relevance of the above‐mentioned recent findings by Edwards et al on this pathway is unclear, one could hypothesize a similar oxidative stress‐related formation of reactive intermediates.…”

“…Both 2 and 3 were, however, more stable to resist autoxidation, and 3 even required the addition of K 3 Fe(CN) 6 or H 2 O 2 and horseradish peroxidase (forming ROS) to transform to a bisdemetoxy‐spiroepoxide ( 3k ), and stop at that phase without converting to a bicyclopentadione . In view of most recent studies, however, it seems that a great deal of the bioactivity of curcuminoids is connected rather to the intermediates of the autoxidation and not the stable bicyclopentadiones . Sanidad et al found that, while curcumin ( 1 ) had potent antiproliferative and proapoptotic activity against colon cancer cells, and exerted anti‐inflammatory activity through inhibition of the NF‐κB signaling, both the mixture of the degradation products and 1r were weaker or rather inactive in these bioassays .…”

“…165 In view of most recent studies, however, it seems that a great deal of the bioactivity of curcuminoids is connected rather to the intermediates of the autoxidation and not the stable bicyclopentadiones. 166,167 Sanidad et al found that, while curcumin (1) had potent antiproliferative and proapoptotic activity against colon cancer cells, and exerted anti-inflammatory activity through inhibition of the NF-κB signaling, both the mixture of the degradation products and 1r were weaker or rather inactive in these bioassays. 166 However, by using an experimental setup that allowed in situ formation of the autoxidized products, Edwards et al found that NF-κB inhibition by curcumin depends on oxidative activation, and that this is due to the reactive electrophile intermediates covalently binding to signaling proteins, such as for example IKKβ.…”

Polymersome‐assisted delivery of curcumin: A suitable approach to decrease cancer stemness markers and regulate miRNAs expression in HT29 colorectal cancer cells

“…It is worth noting that curcumin is the major active compound of the plant with no distinguishable toxicity . Recent studies have shown that curcumin has antiviral, antibacterial, anti‐inflammatory, and antioxidant activities. Furthermore, the therapeutic effects of curcumin and curcumin derivatives have been proven in numerous diseases such as endometriosis, Crohn's disease, pulmonary diseases, cardiac diseases, and kidney diseases .…”