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Curcumin-induced antiproliferative and proapoptotic effects in melanoma

9th January 2007 by Arrow Durfee Posted in Uncategorized

www3.interscience.wiley.com/cgi-bin/abstract/110558137/ABSTRACT

Original Article
Curcumin-induced antiproliferative and proapoptotic effects in melanoma cells are associated with suppression of IB kinase and nuclear factor B activity and are independent of the B-Raf/mitogen-activated/extracellular signal-regulated protein kinase pathway and the Akt pathway

Doris R. Siwak, M.S., Shishir Shishodia, Ph.D., Bharat B. Aggarwal, Ph.D., Razelle Kurzrock, M.D. *
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
email: Razelle Kurzrock (rkurzroc@mdanderson.org)
*Correspondence to Razelle Kurzrock, Unit 422, The University of Texas M. D. Anderson Cancer Center, P.O. Box 301402, Houston, TX 77230-1402
Fax: (713) 563-0566

KEYWORDS
curcumin • nuclear factor B • melanoma • signaling pathways

ABSTRACT

BACKGROUND
Nuclear factor-B (NF-B) plays a central role in cell survival and proliferation in human melanoma; therefore, the authors explored the possibility of exploiting NF-B for melanoma treatment by using curcumin, an agent with known, potent, NF-B-inhibitory activity and little toxicity in humans.

METHODS
Three melanoma cell lines (C32, G-361, and WM 266-4), all of which had B-raf mutations, were treated with curcumin, and the authors assessed its effects on viability ((3-[4,5-dimethylthiazol-2-yl]2,5-diphenyltetrazolium bromide assay) and apoptosis (flow-cytometric analysis of annexin V/propidium iodide-stained cells). Curcumin-treated cells also were examined for NF-B binding activity (electrophoretic mobility shift assay) and for the activity of its upstream regulator, IB kinase (IKK) (immune complex kinase assay). In addition, relevant signaling, as reflected by B-Raf kinase activity (kinase cascade assay), and steady-state levels of activated, downstream effectors, as reflected by mitogen-activated signal-regulated protein kinase (MEK), extracellular signal-regulated protein kinase (ERK), and Akt phosphorylation levels (immunoblots), were assessed.

RESULTS
Curcumin treatment decreased cell viability of all 3 cell lines in a dose-dependent manner (50% inhibitory concentration = 6.1-7.7 M) and induced apoptosis. NF-B and IKK were active constitutively in all melanoma cell lines examined, and curcumin, under apoptosis-inducing conditions, down-regulated NF-B and IKK activities. However, curcumin did not inhibit the activities of B-Raf, MEK, or ERK, and Akt phosphorylation was enhanced. Furthermore, in the presence of curcumin, the Akt inhibitor 1L-6-hydroxymethyl-chiro-inositol 2-[(R)-2-O-methyl-3-O-octadecylcarbonate] no longer suppressed Akt phosphorylation.

CONCLUSIONS
Curcumin has potent antiproliferative and proapoptotic effects in melanoma cells. These effects were associated with the suppression of NF-B and IKK activities but were independent of the B-Raf/MEK/ERK and Akt pathways. Cancer 2005. © 2005 American Cancer Society.

Received: 1 October 2004; Revised: 7 March 2005; Accepted: 14 April 2005

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