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

Abstract

BACKGROUND:

Nuclear factor-kappaB (NF-kappaB) plays a central role in cell survival and proliferation in human melanoma; therefore, the authors explored the possibility of exploiting NF-kappaB for melanoma treatment by using curcumin, an agent with known, potent, NF-kappaB-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-kappaB binding activity (electrophoretic mobility shift assay) and for the activity of its upstream regulator, IkappaB 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 microM) and induced apoptosis. NF-kappaB and IKK were active constitutively in all melanoma cell lines examined, and curcumin, under apoptosis-inducing conditions, down-regulated NF-kappaB 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-kappaB and IKK activities but were independent of the B-Raf/MEK/ERK and Akt pathways.

• Authors: Doris R Siwak, Shishir Shishodia, Bharat B Aggarwal, Razelle Kurzrock
• Journal: Cancer (Cancer) Vol. 104 Issue 4 Pg. 879-90 (Aug 15 2005) ISSN: 0008-543X [Print] United States
• PMID: 16007726 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Interleukin-8
• NF-kappa B
• Proto-Oncogene Proteins
• AKT1 protein, human
• BRAF protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins B-raf
• Proto-Oncogene Proteins c-akt
• CHUK protein, human
• I-kappa B Kinase
• IKBKB protein, human
• IKBKE protein, human
• Extracellular Signal-Regulated MAP Kinases
• Curcumin

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Curcumin (pharmacology)
• Dose-Response Relationship, Drug
• Electrophoretic Mobility Shift Assay
• Extracellular Signal-Regulated MAP Kinases (drug effects, metabolism)
• Flow Cytometry
• Humans
• I-kappa B Kinase
• Interleukin-8 (metabolism)
• Melanoma (drug therapy, metabolism)
• NF-kappa B (drug effects, metabolism)
• Protein Serine-Threonine Kinases (drug effects, metabolism)
• Proto-Oncogene Proteins (drug effects, metabolism)
• Proto-Oncogene Proteins B-raf (drug effects, metabolism)
• Proto-Oncogene Proteins c-akt
• Signal Transduction (drug effects, physiology)