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. 2011 Dec 15;82(12):1901-9.
doi: 10.1016/j.bcp.2011.09.001. Epub 2011 Sep 8.

Suppression of pro-inflammatory and proliferative pathways by diferuloylmethane (curcumin) and its analogues dibenzoylmethane, dibenzoylpropane, and dibenzylideneacetone: role of Michael acceptors and Michael donors

Preetha Anand  1 , Bokyung Sung, Ajaikumar B Kunnumakkara, Kallikat N Rajasekharan, Bharat B Aggarwal
Affiliations

Suppression of pro-inflammatory and proliferative pathways by diferuloylmethane (curcumin) and its analogues dibenzoylmethane, dibenzoylpropane, and dibenzylideneacetone: role of Michael acceptors and Michael donors

Preetha Anand et al. Biochem Pharmacol. .

Retraction in

Abstract

Curcumin, a diferuloylmethane, has been shown to exhibit anti-inflammatory and anti-proliferative activities. Whereas curcumin has both a Michael acceptor and a Michael donor units, its analogues dibenzoylmethane (DBM, a component of licorice) and dibenzoylpropane (DBP) have a Michael donor but not a Michael acceptor unit, and the analogue dibenzylideneacetone (DBA) has a Michael acceptor unit. In the current report, we investigated the potency of DBM, DBP, and DBA in relation to curcumin for their ability to suppress TNF-induced NF-κB activation, NF-κB-regulated gene products, and cell proliferation. We found that all four agents were active in suppressing NF-κB activation; curcumin was most active and DBM was least active. When examined for its ability to inhibit the direct DNA binding activity of p65, a subunit of NF-κB, only DBP inhibited the binding. For inhibition of TNF-induced IKK activation, DBA was most active. For suppression of TNF-induced expression of NF-κB-regulated gene products such as COX-2 (inflammation marker), cyclin D1 (proliferation marker), and VEGF (angiogenesis marker), DBA and curcumin were more active than DBM. Similarly for suppression of proliferation of leukemia (KBM-5), T cell leukemia (Jurkat), prostate (DU145), and breast (MDA-MB-231) cancer cells, curcumin and DBA were most active and DBP was least active. Overall, our results indicate that although curcumin and its analogues exhibit activities to suppress inflammatory pathways and cellular proliferation, a lack of Michael acceptor units in DBM and DBP can reduce their activities.

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Figures

Fig. 1
Fig. 1
The chemical structures of curcumin, dibenzoylmethane (DBM), dibenzylideneacetone (DBA) and 1,3-dibenzoylpropane (DBP).
Fig. 2
Fig. 2
Curcumin and its structural analogues block NF-κB activation induced by TNF-α. KBM-5 cells were preincubated with the indicated concentrations of DBM (A), curcumin (B), DBA (C), and DBP (D) for 4 h and then treated with 0.1 nM TNF-α for 30 min. The nuclear extracts were prepared and assayed for NF-κB activation by EMSA. Cell viability (C.V.) was determined by the trypan blue exclusion assay. (E–H) Time-dependent effect of curcumin, DBA, DBM, and DBP on TNF-α–induced NF-κB activation. KBM-5 cells were preincubated with DBM (panel E; 200 μM), curcumin (panel F; 50 μM), DBA (panel G; 50 μM) and DBP (panel H; 100 μM) for the indicated times and then treated with 0.1 nM TNF-α for 30 min. The nuclear extracts were prepared and assayed for NF-κB activation by EMSA.
Fig. 2
Fig. 2
Curcumin and its structural analogues block NF-κB activation induced by TNF-α. KBM-5 cells were preincubated with the indicated concentrations of DBM (A), curcumin (B), DBA (C), and DBP (D) for 4 h and then treated with 0.1 nM TNF-α for 30 min. The nuclear extracts were prepared and assayed for NF-κB activation by EMSA. Cell viability (C.V.) was determined by the trypan blue exclusion assay. (E–H) Time-dependent effect of curcumin, DBA, DBM, and DBP on TNF-α–induced NF-κB activation. KBM-5 cells were preincubated with DBM (panel E; 200 μM), curcumin (panel F; 50 μM), DBA (panel G; 50 μM) and DBP (panel H; 100 μM) for the indicated times and then treated with 0.1 nM TNF-α for 30 min. The nuclear extracts were prepared and assayed for NF-κB activation by EMSA.
Fig. 3
Fig. 3
The direct effect of curcumin and its analogues on NF-κB complex. Nuclear extracts were prepared from untreated cells or cells treated with 0.1 nM TNF-α and then incubated for 30 min with the indicated concentrations of DBM (A), curcumin (B), DBA (C), and DBP (D). They were then assayed for NF-κB activation by EMSA.
Fig. 4
Fig. 4
Glutathione abrogates curcumin-mediated inhibition of NF-κB but has no effect on DBA-, DBM-, or DBP-mediated inhibition of NF-κB. KBM-5 cells were incubated with 10 mM GSH for 2 h and treated with 100 μM DBP, 50 μM DBA, 200 μM DBM and 50 μM curcumin for 4 h. Then the cells were activated with 0.1 nM TNF-α for 30 min and subjected to EMSA assay for NF-κB activation. Cell viability (C.V.) was determined by the trypan blue exclusion assay.
Fig. 5
Fig. 5
Curcumin and its analogues inhibit IKK activity directly. Whole-cell extracts were prepared from KBM-5 cells treated with 1 nmol/L TNF-α and immunoprecipitated with anti-IKK-β antibody. The immunocomplex kinase assay was performed in the absence or presence of the indicated concentrations of DBA (A), curcumin (B), DBM (C), and DBP (D). To examine the effect of curcumin and its analogues on the level of expression of IKK proteins, whole-cell extracts were fractionated on SDS-PAGE and examined by Western blot analysis using anti-IKK-α and anti-IKK-β antibodies.
Fig. 6
Fig. 6
(A) Curcumin, DBA, DBM and DBP inhibit TAK-1–induced NF-κB-reporter gene (SEAP) expression. A293 cells were transiently transfected with a NF-κB–containing plasmid linked to the SEAP gene or co-transfected with TAK1/TAB1 gene plasmid along with NF-κB-SEAP–containing plasmid, and then treated with DBM (200 μM), curcumin (50 μM), DBA (50 μM), or DBP (100 μM) for 4 h. Cell supernatants were collected and assayed for SEAP activity. Results are expressed as fold activity over the activity of the vector control. Columns, mean of three measurements; bars, SD. *P < 0.05; *P < 0.01 versus TAK1/TAB1 transfection. (B) Effect of curcumin, DBA, DBM, and DBP on NF-κB–dependent gene expression. KBM-5 cells were incubated with the indicated concentrations of each compound for 4 h and then treated with 1 nmol/L TNF-α for 20 h. Whole-cell extracts were prepared and subjected to western blot analysis using antibodies against COX-2, cyclin D1, and VEGF. The same blots were stripped and reprobed with β-actin antibody to verify equal protein loading.
Fig. 7
Fig. 7
Effect of curcumin, DBA, DBM, and DBP on cell proliferation. (A) Five thousand KBM-5, Jurkat, MDA-MB-231 and DU145 cells per well were seeded in triplicate onto 96-well plates and treated with each compound at 1, 5, 10, 25, 50, 100, or 200 μM for 72 h. Cell viability was then measured by the MTT method and presented as percent cell viability. (B) The percent change in cell viability at 25 and 50 μM for each compound is shown. The results are expressed as the mean ± standard error of 3 independent experiments.
Fig. 8
Fig. 8. Michael acceptor donor chemistry
EWG; electron withdrawing group.
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