Curcumin impairs tumor suppressor p53 function in colon cancer cells

Moos, Philip J.; Edes, Kornelia; Mullally, James E.; Fitzpatrick, F. A.

doi:10.1093/carcin/bgh163

Cited by 102 publications

(83 citation statements)

References 29 publications

(22 reference statements)

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“…Others have noted that curcumin can exhibit some blood-thinning properties such as suppression of platelet aggregation, although it remains to be established whether curcumin interacts in any way with blood-thinning drugs. Although several published studies suggest that curcumin may beneficially induce apoptosis in part through its induction of p53 expression [198], at least two other studies suggest that curcumin may instead have a deleterious, antiapoptotic effect by downregulating p53 [199,200]. Similarly, although dozens of studies indicate that curcumin potentiates the effect of chemotherapeutic agents, at least one study done in mice suggests that a curcuminsupplemented diet may inhibit the antiproliferative effects of cyclophosphamide on breast cancer growth (the investigators in that study, however, monitored tumor growth for only 3 days) Q9 [201].…”

Section: Adverse Effects Of Curcuminmentioning

confidence: 99%

Curcumin as “Curecumin”: From kitchen to clinic

Goel

Kunnumakkara

Aggarwal

2008

Biochemical Pharmacology

1,917

1,290

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Section: Adverse Effects Of Curcuminmentioning

confidence: 99%

Curcumin as “Curecumin”: From kitchen to clinic

Goel

Kunnumakkara

Aggarwal

2008

Biochemical Pharmacology

1,917

1,290

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“…This reaction may explain, for instance, why curcumin generates ROS by irreversibly modifying the antioxidant enzyme thioredoxin reductase, 49 why curcumin induces topoisomerase II-mediated DNA damage, 10,54,55 and why curcumin inactivates the tumor suppressor protein p53. 56,57 Several other lines of evidence raise concern about curcumin safety. Curcumin was recently found to be an active iron chelator in vivo and to induce a state of overt iron deficiency anemia in mice fed with diets poor in iron.…”

Section: Dear Editormentioning

confidence: 99%

The dark side of curcumin

Burgos-Morón

Calderón-Montaño

Salvador

et al. 2010

Intl Journal of Cancer

297

210

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Dear Editor,Curcumin is a yellow-orange pigment obtained from the plant Curcuma longa. The powdered rhizome of this plant, called turmeric, is a common ingredient in curry powders and has a long history of use in traditional Asian medicine for a wide variety of disorders. In the last decade a large number of reports have been published on the beneficial effects of curcumin, and it has repeatedly been claimed that this natural product is efficient and safe for the prevention and treatment of several diseases including cancer. 1-3 It is not surprising, therefore, that curcumin is currently sold as a dietary supplement and that numerous clinical trials are ongoing or recruiting participants to evaluate curcumin activity. But there is accumulating evidence that curcumin may not be so effective and safe. Because such evidence is not generally acknowledged, the purpose of this letter is to briefly review the negative properties of curcumin so that they can be balanced against its beneficial effects.Most of the evidence that supports the therapeutic potential of curcumin is mainly based on in vitro studies in which curcumin was tested at concentrations in the micromolar range. Several reports have demonstrated, however, that the plasma concentrations of curcumin in people taking relatively high oral doses of this compound are very low, typically in the nanomolar range (reviewed in Ref. 4). For instance, a recent study examined the pharmacokinetics of a curcumin preparation in 12 healthy human volunteers 0.25-72 hr after an oral dose of 10 or 12 g. Using a high-performance liquid chromatography assay with a limit of detection of 50 ng mL À1 , only 1 subject had detectable free curcumin at any of the time points assayed. 5 The fact that curcumin also undergoes extensive metabolism in intestine and liver 6,7 means that high concentrations of curcumin cannot be achieved and maintained in plasma and tissues after oral ingestion. This is a major obstacle for the clinical development of this agent and suggests that the therapeutic potential of oral curcumin is limited. The low clinical efficiency of curcumin in the treatment of several chronic diseases such as Alzheimer's disease and cardiovascular diseases has been discussed recently. 8 As far as cancer is concerned, in vitro studies have demonstrated that cancer cells do not die unless they are exposed to curcumin concentrations of 5-50 lM for several hours. 4,9,10 Because of its poor bioavailability, these concentrations are not achieved outside the gastrointestinal tract when curcumin is taken orally. Because of its extensive metabolism in intestine and liver, these concentrations cannot be maintained for several hours in the gastrointestinal tract. This suggests that the chemotherapeutic potential of oral curcumin is limited even for the treatment of cancers of the gastrointestinal tract. Accordingly, when 15 patients with advanced colorectal cancer were treated with curcumin at daily doses of 3.6 g for up to 4 months, no partial responses to treatment or decreases in tu...

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“…The effects reported for curcumin include induced accumulation of WT p53 and induction of apoptosis in the human breast cancer cell lines MCF7 and TR9-7 (26,27) and human neuroblastoma cell lines (28). However, in etoposidetreated human RKO colorectal cancer cell line, curcumin was reported to inhibit accumulation of Ser-15 phosphorylated WT p53 and to inhibit induction of G 1 growth arrest (29). In view of these apparently contradictory reported effects of curcumin on p53 accumulation and function in different human cancer cell lines, we have studied the effect of curcumin on the stability of p53 in different cells.…”

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confidence: 99%

Inhibition of NAD(P)H:quinone oxidoreductase 1 activity and induction of p53 degradation by the natural phenolic compound curcumin

Tsvetkov

Asher

Reiss

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

137

113

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NAD(P)H:quinone oxidoreductase 1 (NQO1) regulates the stability of the tumor suppressor WT p53. NQO1 binds and stabilizes WT p53, whereas NQO1 inhibitors including dicoumarol and various other coumarins and flavones induce ubiquitin-independent proteasomal p53 degradation and thus inhibit p53-induced apoptosis. Here, we show that curcumin, a natural phenolic compound found in the spice turmeric, induced ubiquitin-independent degradation of WT p53 and inhibited p53-induced apoptosis in normal thymocytes and myeloid leukemic cells. Like dicoumarol, curcumin inhibited the activity of recombinant NQO1 in vitro, inhibited the activity of endogenous cellular NQO1 in vivo, and dissociated NQO1-WT p53 complexes. Neither dicoumarol nor curcumin dissociated the complexes of NQO1 and the human cancer hot-spot p53 R273H mutant and therefore did not induce degradation of this mutant. NQO1 knockdown by small-interfering RNA induced degradation of both WT p53 and the p53 R273H mutant. The results indicate that curcumin induces p53 degradation and inhibits p53-induced apoptosis by an NQO1-dependent pathway.NQO1-dependent pathway ͉ disruption of NQO1-p53 binding ͉ cancer hot-spot p53 mutant ͉ p53-induced apoptosis W ild-type p53 is a labile tumor suppressor protein whose cellular level is mainly regulated by its rate of proteasomal degradation (reviewed in ref. 1). WT p53 protein can induce growth arrest (1-4) or apoptosis (5-8) and can thus prevent accumulation of DNA-damaged cells that could lead to the development of cancer (reviewed in refs. 1, 9, and 10). This tumor-suppressing activity of WT p53 is abolished by mutations in the p53 gene that occur in Ͼ50% of human cancers (1,11,12), and the mutant proteins often accumulate in the cancer cells (13). Degradation of p53 is mediated by two alternative pathways, ubiquitin-independent (14, 15) or ubiquitin-dependent. Ubiquitin-dependent degradation of p53 is mediated by different ubiquitin E3 ligases, including Mdm2 (16,17), Pirh2 (18), and Cop1 (19), that bind and ubiquitinate p53, targeting it to degradation via the 26S proteasome. The ubiquitin-independent pathway is regulated by NAD(P)H:quinone oxidoreductase 1 (NQO1) (14,15,20,21) and is mediated via the 20S proteasome (22). We have shown that NQO1 stabilizes p53, so that NQO1 overexpression increases p53 levels (20, 21), whereas NQO1 knockdown by small interfering RNA (siRNA) decreases the level of p53 (14). NQO1 binds to p53 (23, 24) and dicoumarol, an inhibitor of NQO1 activity that competes with NAD(P)H for binding to NQO1, disrupts NQO1-p53 binding (23), and induces ubiquitin-independent proteasomal degradation of p53 (14,15,20,21,23). Various other coumarins and flavones that also compete with NAD(P)H for binding to NQO1 also induce ubiquitin-independent p53 degradation (23). However, unlike WT p53 and some p53 mutants, the most frequent hot-spot human cancer p53 mutants (11, 12) were resistant to dicoumarolinduced degradation by increased binding to NQO1 (23).Curcumin, a natural phenolic compound found in the spice ...

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Curcumin impairs tumor suppressor p53 function in colon cancer cells

Cited by 102 publications

References 29 publications

Curcumin as “Curecumin”: From kitchen to clinic

Curcumin as “Curecumin”: From kitchen to clinic

The dark side of curcumin

Inhibition of NAD(P)H:quinone oxidoreductase 1 activity and induction of p53 degradation by the natural phenolic compound curcumin

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