Curcumin induces irreversible growth inhibition and apoptosis in melanoma cell lines
Doris R. Siwak, Razelle Kurzrock.
The University of Texas M. D. Anderson Cancer Center, Houston, TX.
Curcumin [1,7-bis(4-hydroxy-3-methoxy phenyl)-1,6-heptadine-3,5-dione], a food additive isolated from the spice turmeric, has significant anti-inflammatory, antioxidant, and antitumor activity, and is demonstrated to be nontoxic after oral or topical administration in animal and early-phase human studies.
Because of the limited number of effective therapies available for melanoma and the potential for topical as well as oral treatment, we examined the effects of curcumin on 6 melanoma cell lines (A375, C32, G-361, HT-144, SK-MEL-2, and WM 266-4).
As measured by the MTT cell proliferation assay, cells treated by curcumin for 72-96 hours (~3 cell doublings, depending on the cell line) were significantly growth inhibited compared to control cells (treated with 0.1% DMSO only), with 50% inhibitory concentrations (IC50s) of 6.1-8.3 mM and IC90s of 15.3-21.4 mM for the cell lines tested.
Replating curcumin-treated cells in curcumin-free medium followed by subsequent determination of cell growth via MTT assay after 72-96 hours revealed that growth inhibition by curcumin at concentrations ģIC50 is irreversible.
Flow cytometric analysis of annexin V-positive/propidium iodide-negative cells showed that curcumin treatment after 48-72 hours (~2 cell doublings) at 10 mM increased the proportion of apoptotic cells 1.9-13-fold (G-361 and A375, respectively) while 20 mM treatment increased apoptosis 7.2-20-fold (G-361 and WM 266-4, respectively) compared to DMSO control
. Previous reports have suggested that curcumin acts via inhibition of NF-kB, a survival protein constitutively activated in melanoma cells.
However, while curcumin treatment at 10 mM for 48-72 hours suppressed NF-kB binding as assessed by EMSA in 3 of 5 cell lines (C32, G-361, WM 266-4), no change compared to DMSO control was observed in HT-144 cells, and increased NF-kB binding was observed in A375 cells. A375 cells treated 12, 24, or 48 hours after curcumin exposure showed a progressive increase in NF-kB binding compared to control, suggesting that curcumin does not variably modulate NF-kB binding in these cells.
Our results indicate that curcumin has potent cytotoxic/pro-apoptotic effects in melanoma cells and suggest that these effects are mediated via NF-kB-dependent and independent pathways.
Further exploration of the mechanism of action of curcumin is underway as are studies in murine melanoma models and plans to initiate a clinical trial in melanoma.
AACR Abstract Number: R2722 , 2003
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