A monoterpene, unique component of thyme honeys, induces apoptosis in prostate cancer cells via inhibition of NF-κB activity and IL-6 secretion

doi:10.1016/j.phymed.2014.04.032

Abstract

We have previously demonstrated that Greek thyme honey inhibits significantly the cell viability of human prostate cancer cells. Herein, 15 thyme honey samples from several regions of Greece were submitted to phytochemical analysis for the isolation, identification and determination (through modern spectral means) of the unique thyme honey monoterpene, the compound trihydroxy ketone E-4-(1,2,4-trihydroxy-2,6,6-trimethylcyclohexyl)-but-3-en-2-one.

We investigated the anti-growth and apoptotic effects of the trihydroxy ketone on PC-3 human androgen independent prostate cancer cells using MTT assay and Annexin V-FITC respectively. The molecular pathways involved to such effects were further examined by evaluating its ability to inhibit (a) the NF-κB phosphorylation (S536), (b) JNK and Akt phosphorylation (Thr183/Tyr185 and S473 respectively) and (c) IL-6 production, using ELISA method. The anti-microbial effects of the trihydroxy ketone against a panel of nine pathogenic bacteria and three fungi were also assessed.

The trihydroxy ketone exerted significant apoptotic activity in PC-3 prostate cancer cells at 100 μM, while it inhibited NF-κB phosphorylation and IL-6 secretion at a concentration range 10⁻⁶–10⁻⁴ M. Akt and JNK signaling were not found to participate in this process. The trihydroxy ketone exerted significant anti-microbial profile against many human pathogenic bacteria and fungi (MIC values ranged from 0.04 to 0.57 mg/ml). Conclusively, the Greek thyme honey-derived monoterpene exerted significant apoptotic activity in PC-3 cells, mediated, at least in part, through reduction of NF-κB activity and IL-6 secretion and may play a key role in the anti-growth effect of thyme honey on prostate cancer cells.

Abbreviations

NF-κB, nuclear factor-kappaB;
mapk, mitogen-activated protein kinase;
PI3K, phosphatidylinositide 3-kinase;
Akt, protein kinase B;
FAK, focal adhesion kinase;
PSG, prostate-specific G-protein-coupled receptor;
IL-6, interleukin-6;
JNK, c-Jun NH(2)-terminal kinase;
TLC, thin layer chromatography;
NMR, nuclear magnetic resonance;
FBS, fetal bovine serum;
DCC, dextran coated charcoal slurry;
RT, room temperature;
GC-MS, gas chromatography–mass spectrometry;
MIC, minimum inhibitory concentration;
AIDS, acquired immunodeficiency syndrome;
PI, propidium iodide;
RI, retention indices;
AP-1, activator protein 1;
CREB, cAMP response element-binding protein;
c/EBP, CCAAT/enhancer binding protein;
SAPK, stress-activated protein kinases

Keywords

Apoptosis;
Interleukin-6;
Monoterpene;
NF-κB;
Prostate cancer cells;
Trihydoxy ketone

: Corresponding author. Tel.: +302107462682.

1: Corresponding author for chemical analysis experiments. Tel.: +30 2107274595; fax: +30 2107274115.

2: Corresponding author for biological studies. Tel.: +30 2107462682; fax: +30 2107462703.

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Wednesday, 27 May 2015