Curcumin induces proapoptotic effects against human melanoma cells and modulates the cellular response to immunotherapeutic cytokines

• Published in: Molecular cancer therapeutics Vol. 8; no. 9; pp. 2726 - 2735
• Main Authors: Bill, Matthew A, Bakan, Courtney, Benson, Jr, Don M, Fuchs, James, Young, Gregory, Lesinski, Gregory B
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01-09-2009
• Subjects: Apoptosis; Apoptosis - drug effects; Blotting, Western; Curcumin; Curcumin - pharmacology; Cytokines - therapeutic use; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Humans; Immunotherapy; Interferon; Interferons - antagonists & inhibitors; Interferons - metabolism; Interleukin; Killer Cells, Natural - drug effects; Melanoma; Melanoma - pathology; Melanoma - therapy; Phosphorylation; Polymerase Chain Reaction; Signal Transduction; STAT1 Transcription Factor - metabolism; STAT3 Transcription Factor - metabolism; Tumor Cells, Cultured
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-09-0377

Curcumin has potential as a chemopreventative and chemotherapeutic agent, but its interactions with clinically relevant cytokines
are poorly characterized. Because cytokine immunotherapy is a mainstay of treatment for malignant melanoma, we hypothesized
that curcumin could modulate the cellular responsiveness to interferons and interleukins. As a single agent, curcumin induced
a dose-dependent increase in apoptosis of human melanoma cell lines, which was most prominent at doses >10 μmol/L. Immunoblot
analysis confirmed that curcumin induced apoptosis and revealed caspase-3 processing, poly ADP ribose polymerase cleavage,
reduced Bcl-2, and decreased basal phosphorylated signal transducers and activators of transcription 3 (STAT3). Despite its
proapoptotic effects, curcumin pretreatment of human melanoma cell lines inhibited the phosphorylation of STAT1 protein and
downstream gene transcription following IFN-α and IFN-γ as determined by immunoblot analysis and real time PCR, respectively.
Pretreatment of peripheral blood mononuclear cells from healthy donors with curcumin also inhibited the ability of IFN-α,
IFN-γ, and interleukin-2 to phosphorylate STAT proteins critical for their antitumor activity (STAT1 and STAT5, respectively)
and their respective downstream gene expression as measured by real time PCR. Finally, stimulation of natural killer (NK)
cells with curcumin reduced the level of interleukin-12–induced IFN-γ secretion, and production of granzyme b or IFN-γ upon
coculture with A375 melanoma cells or NK-sensitive K562 cells as targets. These data show that although curcumin can induce
apoptosis of melanoma cells, it can also adversely affect the responsiveness of immune effector cells to clinically relevant
cytokines that possess antitumor properties. [Mol Cancer Ther 2009;8(9):2726–35]