Contribution of Degradation Products to the Anticancer Activity of Curcumin

Shen, Liang; Ji, Hong‐Fang

doi:10.1158/1078-0432.ccr-09-1749

Cited by 35 publications

(24 citation statements)

References 4 publications

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“…Indeed, ferulic acid at high doses acted in opposite fashion as compared to curcuminoids and stimulated, rather than suppressed, breast cancer cell PTHrP secretion. Consistent with our findings, vanillin and ferulic acid, even at high concentrations, have been demonstrated by others to have minimal effect on other known curcuminoid targets, including cyclooxygenase enzyme and NF-κB [37–40], suggesting that these metabolites are not mediating curcuminoid biological effects. What is more, vanillin and ferulic acid have not been identified as abundant degradation products of curcuminoids in vitro [19,41,42] and are not reported to be major metabolites in vivo [21,22], casting further doubt on the postulate that vanillin and ferulic acid are responsible for the bioactivity of curcuminoids.…”

Section: Discussionsupporting

confidence: 92%

Bioactivity of Turmeric-derived Curcuminoids and Related Metabolites in Breast Cancer

Wright¹,

Frye²,

Gorti³

et al. 2013

CPD

123

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While the chemotherapeutic effect of curcumin, one of three major curcuminoids derived from turmeric, has been reported, largely unexplored are the effects of complex turmeric extracts more analogous to traditional medicinal preparations, as well as the relative importance of the three curcuminoids and their metabolites as anti-cancer agents. These studies document the pharmacodynamic effects of chemically-complex turmeric extracts relative to curcuminoids on human breast cancer cell growth and tumor cell secretion of parathyroid hormone-related protein (PTHrP), an important driver of cancer bone metastasis. Finally, relative effects of structurally-related metabolites of curcuminoids were assessed on the same endpoints. We report that 3 curcuminoid-containing turmeric extracts differing with respect to the inclusion of additional naturally occurring chemicals (essential oils and/or polar compounds) were equipotent in inhibiting human breast cancer MDA-MB-231 cell growth (IC50=10–16μg/mL) and secretion of osteolytic PTHrP (IC50=2–3μg/mL) when concentrations were normalized to curcuminoid content. Moreover, these effects were curcuminoid-specific, as botanically-related gingerol containing extracts had no effect. While curcumin and bis-demethoxycurcumin were equipotent to each other and to the naturally occurring curcuminoid mixture (IC50=58 μM), demethoxycurcumin was without effect on cell growth. However, each of the individual curcuminoids inhibited PTHrP secretion (IC50=22–31μM) to the same degree as the curcuminoid mixture (IC50=16 μM). Degradative curcuminoid metabolites (vanillin and ferulic acid) did not inhibit cell growth or PTHrP, while reduced metabolites (tetrahydrocurcuminoids) had inhibitory effects on cell growth and PTHrP secretion but only at concentrations ≥10-fold higher than the curcuminoids. These studies emphasize the structural and biological importance of curcuminoids in the anti-breast cancer effects of turmeric and contradict recent assertions that certain of the curcuminoid metabolites studied here mediate these anti-cancer effects.

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Section: Discussionsupporting

confidence: 92%

Bioactivity of Turmeric-derived Curcuminoids and Related Metabolites in Breast Cancer

Wright¹,

Frye²,

Gorti³

et al. 2013

CPD

123

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“…In a recent debate initiated by comments on the results of Dhillon et al on the potential therapeutic use of large doses of orally administered curcumin in cancer patients, the same degradation products were hypothesized to be responsible for its beneficial effect . 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 .…”

Section: Biological Significance Of Rons Scavenging‐related Antioxidamentioning

confidence: 99%

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

Hunyadi

2019

Medicinal Research Reviews

164

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Small molecule, dietary antioxidants exert a remarkably broad range of bioactivities, and many of these can be explained by the influence of antioxidants on the redox homeostasis. Such compounds help to modulate the levels of harmful reactive oxygen/nitrogen species, and therefore participate in the regulation of various redox signaling pathways. However, upon ingestion, antioxidants usually undergo extensive metabolism that can generate a wide range of bioactive metabolites. This makes it difficult, but otherwise a need, to identify the ones responsible for the different activities of antioxidants. By better understanding their ways of action, the use of antioxidants in therapy can be improved. This review provides a summary on the role of the in vivo metabolic changes and the oxidized metabolites on the mechanisms behind the bioactivity of antioxidants. A special attention is given to metabolites described as products of biomimetic oxidative chemical reactions, which can be considered as models of free radical scavenging. During such reactions a wide variety of metabolites are formed, and they can exert completely different specific bioactivities as compared to their parent antioxidants. This implies that exploring the free radical scavenging‐related metabolite fingerprint of each antioxidant molecule, collectively defined here as the scavengome, will lead to a deeper understanding of the bioactivity of these compounds. Furthermore, this paper aims to be a working tool for systematic studies on oxidized metabolic fingerprints of antioxidants, which will certainly reveal an often‐neglected segment of chemical space that is a treasury of bioactive compounds.

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“…Thus, it has been suggested that some of its biological effects are mediated by metabolites (Ireson et al, 2001; Anand et al, 2008; Shen and Ji, 2009, 2012). Curcumin can undergo spontaneous autoxidation in aqueous solutions at physiological pH (Figure 9) (Griesser et al, 2011), and this reaction gives rise to novel quinone-containing products that have potential for biological activity.…”

Section: Curcuminmentioning

confidence: 99%

Phytochemicals as anticancer and chemopreventive topoisomerase II poisons

2013

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Phytochemicals are a rich source of anticancer drugs and chemopreventive agents. Several of these chemicals appear to exert at least some of their effects through interactions with topoisomerase II, an essential enzyme that regulates DNA supercoiling and removes knots and tangles from the genome. Topoisomerase II-active phytochemicals function by stabilizing covalent protein-cleaved DNA complexes that are intermediates in the catalytic cycle of the enzyme. As a result, these compounds convert topoisomerase II to a cellular toxin that fragments the genome. Because of their mode of action, they are referred to as topoisomerase II poisons as opposed to catalytic inhibitors. The first sections of this article discuss DNA topology, the catalytic cycle of topoisomerase II, and the two mechanisms (interfacial vs. covalent) by which different classes of topoisomerase II poisons alter enzyme activity. Subsequent sections discuss the effects of several phytochemicals on the type II enzyme, including demethyl-epipodophyllotoxins (semisynthetic anticancer drugs) as well as flavones, flavonols, isoflavones, catechins, isothiocyanates, and curcumin (dietary chemopreventive agents). Finally, the leukemogenic potential of topoisomerase II-targeted phytochemicals is described.

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Contribution of Degradation Products to the Anticancer Activity of Curcumin

Cited by 35 publications

References 4 publications

Bioactivity of Turmeric-derived Curcuminoids and Related Metabolites in Breast Cancer

Bioactivity of Turmeric-derived Curcuminoids and Related Metabolites in Breast Cancer

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

Phytochemicals as anticancer and chemopreventive topoisomerase II poisons

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