Docosahexaenoic acid enhances the efficacy of docetaxel in prostate cancer cells by modulation of apoptosis: the role of genes associated with the NF-kappaB pathway.
BACKGROUND
Evidence is growing for beneficial interactions between omega-3 fatty acids from fish and chemotherapy agents in certain human cancers. Evidence for similar effects in prostate cancer is lacking. We investigated the effects of docosahexaenoic acid (DHA-22:6n-3), a component of fish oil, on the cytotoxicity of docetaxel in prostate cancer cells.


METHODS
Cell viability was studied using the MTT assay and apoptosis was evaluated by flow cytometry using PI, annexin V, and JC-1 staining. Cellular signaling mechanisms that might explain the observed pro-apoptotic effects were investigated using NF-kappaB pathway specific cDNA microarrays and RT-PCR validation.


RESULTS
DHA enhanced the pro-apoptotic efficacy of docetaxel, synergistically, in hormone receptor positive and negative LNCaP, DU145 and PC3 cells, respectively. Cell cycle analysis showed an increase in G2M arrest and JC-1 staining showed a significant (P < 0.018) increase in apoptotic cells with combination treatments in LNCaP cells. Microarray and RTPCR showed decreased expression of FADD, AKT1, MAX, TRAF3, MAP2k4, TNFRSF11A, and RIPK1 in LNCaP cells. Similar results were obtained with DU145 cells; combinations were more effective than single treatments. Combination treatments suppressed NF-kappaB signaling that was induced by docetaxel alone; this is considered an anti-apoptotic response.


CONCLUSIONS
DHA synergistically enhanced the cytotoxic effect of docetaxel in prostate cancer cells through increased apoptosis by suppression of genes involved in the NF-kappaB pathway. This highlights the possibility of developing such combination modalities for treatment of prostate cancer.
Shaikh
Irshad A A
IA
School of Medicine and Dentistry, Cancer Medicine Research Group, University of Aberdeen, Medical School, Foresterhill, Aberdeen, UK.
Brown
Iain
I
Schofield
Andrew C
AC
Wahle
Klaus W J
KW
Heys
Steven D
SD
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D043823:Taxoids / Q000494:pharmacology*
D000970:Antineoplastic Agents; D016328:NF-kappa B; D043823:Taxoids; D000077143:Docetaxel; D004281:Docosahexaenoic Acids